Eur J Cardiothorac Surg 2006;30:499-507
© 2006 Elsevier Science NL
The key role of apoptosis in the pathogenesis and treatment of pulmonary hypertension
Emin Gurbanova,*,
Xiao Shiliangb,1
a Huazhong University of Science and Technology, Tongji Medical College, Union Hospital, Department of Cardiovascular Surgery, Wuhan 430030, PR China
b Huazhong University of Science and Technology, Union Hospital, Department of Cardiovascular Surgery, Wuhan 430030, PR China
Received 8 March 2006;
received in revised form 8 May 2006;
accepted 15 May 2006.
* Corresponding author. Tel.: +86 83691185. (Email: emin_cn{at}yahoo.com; shi_liangxiao{at}yahoo.com).
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Abstract
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In recent years, the process of the programmed cell death has gained much interest because it has important pathophysiological consequences contributing to the deletion of unwanted cells in the vessel wall, loss of pulmonary smooth muscle cells and therefore in reversing the pulmonary pressure. For the reason that most patients with pulmonary hypertension present with limited reversibility with vasodilators, antiremodeling approach for treatment appears to be feasible. Induction or enhancement of vascular smooth muscle cells apoptosis may be targeted to develop novel therapeutic approaches for pulmonary vascular remodeling in patients with pulmonary hypertension.
This review summarizes the current mechanisms, investigate the roles and provide novel insights into the potential therapeutic value of apoptosis in the pulmonary artery remodeling of pulmonary hypertension.
Key Words: Apoptosis • Remodeling • Pulmonary hypertension • Muscle • Smooth
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1. Pulmonary artery hypertension overview
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Pulmonary arterial hypertension (PAH) is a severe disease with poor prognosis, caused by vasoconstriction, in situ thrombosis and vascular remodeling of small pulmonary arteries inducing a fixed pulmonary arterial obstruction and persistent elevation of pulmonary arterial resistance.
Pulmonary arterial hypertension can be classified into two categories: (1) primary and (2) secondary. Primary pulmonary hypertension (familial and sporadic) is relatively severe and rare. Secondary pulmonary hypertension (SPH), whether from parenchymal lung disease or other etiologies, is more common than primary pulmonary hypertension (PPH). However, both the primary and secondary pulmonary hypertension has identical pathologic features, a similar clinical course [1].
Pulmonary hypertension (PHT) is a progressive and often-fatal disease for which there is little effective treatment at present [2]. Without treatment, the disorder progresses in most cases to right heart failure and death. One of the difficulties in treating patients with PAH is that the subacute nature of disease presentation often prevents an accurate diagnosis during the early stages of the illness. Conventional treatment consists of lifetime administration of anticoagulants, oxygen, diuretics, and digoxin. Vasodilator therapy with calcium channel antagonists is indicated in patients who are ‘vasoreactive’ to acute vasodilator challenge as assessed by right-heart catheterisation. Promising results are obtained by continuous intravenous administration of epoprostenol (prostacyclin). Newer therapies for PPH include prostacyclin analogues, endothelin receptor antagonists, nitric oxide, phosphodiesterase-5 inhibitors, elastase inhibitors, and gene therapy. With current therapies progression of disease is slowed, but not halted. Lung transplantation remains the only treatment option for patients with uncontrollable pulmonary hypertension.
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2. Pathophysiology and pathogenesis of pulmonary hypertension
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Pulmonary arterial hypertension is a disease of the small pulmonary arteries in which the combined effects of pulmonary artery vasoconstriction, vascular remodeling and thrombosis greatly contribute to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH) [3,4]. The pathogenesis of pulmonary arterial hypertension is a complicated, multifactorial process (Fig. 1
). Although growth is the mechanism that is more classically associated with vascular remodeling, it has increasingly been appreciated that apoptosis, low-grade inflammation, and vascular fibrosis are dynamic processes that also may influence the degree of remodeling that occurs [5]. It is notable that tissue remodeling also involves apoptosis to counteract the effects of proliferation. The role and therapeutic value of apoptosis in pulmonary hypertension will be prominently discussed below.
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Fig. 1. Pathophysiologic mechanisms in PAH. Combined effects of pulmonary artery vasoconstriction, vascular remodeling and thrombosis leading to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in PAH. Vascular remodeling involves all the sheaths of the vessel wall and all the cell types of which it is composed (endothelial cells, smooth muscle cells, fibroblasts, inflammatory cells and platelets). Growth, apoptosis, low-grade inflammation, ions and vascular fibrosis are dynamic processes that all may influence the degree of remodeling that occur. Excessive vasoconstriction has been related to a defect in the function of expression of the potassium channels and endothelial dysfunction. This leads to chronic insufficiency in the production of vasodilators, notably nitrogen monoxide and prostacyclin and the excessive production of vasoconstrictors such as endotheline-1.
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2.1 Vascular remodeling
Remodeling is frequently used to describe any structural and functional alteration of blood vessels that would allow them to perform their function more effectively. Remodeling is usually an adaptive process in response to long-term changes in hemodynamic conditions, as occurs during development, but it can also contribute to the pathophysiology of vascular diseases and circulatory disorders. Remodeling may be classified based on the: (1) nature of changes in vessel luminal diameter as vessel enlargement (outward remodeling), vessel narrowing (inward remodeling), alternatively as adaptive (compensatory, appropriate to the hemodynamic stimulus), or maladaptive (dysfunctional, inappropriate); (2) alterations of tunica media mass (increased = hypertrophic, decreased = atrophic, no change = eutrophic) [6]. As an example ‘hypertrophic inward’ remodeling would be defined as a decrease in lumen diameter with increased wall thickness such as may occur with increased pressure. It has been best studied in resistance vessels during hypertension (Fig. 2
). However, varied forms of remodeling frequently may coexist in different vascular beds of the same individual.
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Fig. 2. Schematic classification of vascular remodeling. Remodeling may be classified based on the: (1) nature of changes in vessel luminal diameter as vessel enlargement (outward remodeling), vessel narrowing (inward remodeling); (2) alterations of tunica media mass (increased = hypertrophic, decreased = atrophic, no change = eutrophic). Varied forms of remodeling frequently may coexist in different vascular beds of the same individual.
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Cellular processes underlying events in remodeling include altered vascular smooth muscle cell (VSMC) growth, migration, differentiation and increased extracellular matrix abundance. Artery wall remodeling is a hallmark of severe, advanced pulmonary hypertension, presenting histologically as neointimal proliferation, intimal fibrosis, medial and adventitial hyperplasia and hypertrophy. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur [7–9]. It is accompanied by remodeling of the extracellular matrix (ECM) by proteinases [10,11] and by increased expression and deposition of the ECM components elastin, collagen [12,13] fibronectin [14,15] and tenascin-C (TN) [15,16]. Subsequent intimal thickening, fibrosis and in situ thrombosis, altogether lead to vaso-occlusive alterations referred to as plexiform lesions.
2.2 Impact of remodeling on hypertension
Pulmonary vascular remodeling can be initiated by a variety of stimuli, including chronic hypoxia, increased pulmonary blood flow, collagen vascular disease, anorectic and other drugs, and idiopathic causes. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during this process [17,18]. Moreover, the degree of the structural alteration of the lung vessels varies between species [19].
It is still a matter of debate whether the structural changes of blood vessels precede hypertension and are thus involved in its pathogenesis to some degree or whether they result from the elevation of blood pressure [20–22]. Pulmonary vascular remodeling is leading to increased pulmonary vascular resistance and reduced compliance. This tendency of peripheral vascular beds to increase flow resistance for a given increase of bulk flow or driving pressure may amplify and stabilize blood pressure elevation in the development of hypertension. At the same time microvasculature is an extremely adaptable structure, made up of cellular and noncellular components, that is capable of architectural and functional adjustments in response to multiple biochemical and mechanical stimuli, in which their diameters and wall thicknesses change in response to chronic changes in hemodynamic conditions (as a reduced lumen diameter and consequent increased media:lumen ratio). Inadequate or inappropriate adjustments often result in pathophysiology [23].
As it has been mentioned before, vascular remodeling is an adaptive response to variations in the hemodynamic environment acting on the arterial wall. The structure of blood vessels is not constant but is continually being adjusted to allow them to fulfil their function of delivering blood to the capillaries in the correct quantity and at the correct pressure [24]. At the acute stage, increased neurohumoral activity leads to vasoconstriction and increases blood pressure. Although vasomotor control allows rapid adaptation of lumen diameter, vascular remodeling constitutes an active process that occurs in response to long-term alterations of hemodynamic parameters. In the long run, the increased pressure will be maintained by a normal neurohumoral drive but with an increased wall:lumen ratio, in other words, the situation normally seen in hypertension. To withstand the chronic increase in intraluminal pressure, the vessel wall becomes thickened and stronger. This ‘armouring’ of the vessel wall with extra-smooth muscle and extracellular matrix leads to a decrease in lumen diameter and reduced capacity for vasodilatation. Remodeling of small arteries may increase vascular resistance even at full dilatation, i.e., in the absence of vascular tone [20]. Resulting remodeling of these arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to the pathology of vascular diseases and cardiovascular complications of hypertension [20,23]. The maladaptive response results in an inappropriate increased pulmonary vascular resistance and consequently, sustained pulmonary hypertension. Severe pulmonary hypertension increases right ventricular afterload and eventually leads to the clinical syndrome of right heart failure with systemic congestion and inability to adapt right ventricular output to peripheral demand [25]
. Increased awareness of vascular remodeling may provide new therapeutic insights for the future.
2.3 Vasoconstriction and thrombosis
Excessive vasoconstriction has been related to a defect in the function of expression of the potassium channels and endothelial dysfunction [26]. Endothelial dysfunction leads to chronic insufficiency in the production of vasodilators, notably nitric oxide and prostacyclin and the excessive production of vasoconstrictors such as endothelin (ET)-1. Vascular thrombosis, which has been noted by pathologists in pulmonary hypertension, could be related to an imbalance between thrombotic inducing factors (such as anti-phospholipid antibodies, ET-1 and thromboxane) and decreased fibrinolytic activity and antiaggregant endothelial factors (like prostacyclin, NO, thrombomodulin) [27]. Thus, vasoconstriction and thrombosis contribute to the increase in vascular tonus and pulmonary vascular remodeling. Chronic vasoconstriction may result in an inwardly remodeled blood vessel as the contracted vessel structure becomes embedded in a remodeled extracellular matrix, further promoting re-arrangement of SMCs around a smaller lumen.
Until now, the pathogenesis of pulmonary hypertension is still not fully understood. Abnormalities in the homeostasis of intracellular Ca (2+), transmembrane flux of ions, and membrane potential may play significant roles in the processes leading to pulmonary vascular remodeling. The inhibition of Kv channels results in an accumulation of positively charged K+ ions within the cell, raising the membrane potential to more positive levels (depolarization), which activates the voltage-gated, L-type calcium channel [28]. Calcium then enters the cell, activating the contractile apparatus, leading to vasoconstriction and possibly initiating cell proliferation.
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3. Cellular and molecular mechanisms of apoptosis in pulmonary vascular remodeling
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Apoptosis, or programmed cell death, is a fundamental biological process involved in many physiological and pathological phenomena. Multicellular organisms constantly delete and renew cells to maintain their homeostasis. Dysfunction or abnormal regulation of this process has been implicated in atherosclerosis, cancer, neurodegenerative disorders, and pulmonary vascular disease [29,30]. Death of cells in the normal turnover of tissues permits the removal of cells with genetic damage, those with improper developmental changes, or those that are produced in excess [31,32]. At the cellular and molecular levels, apoptosis is characterized by a distinct series of morphological and biochemical changes that include cell shrinkage, formation of apoptotic bodies, caspase activation, chromatin condensation, DNA fragmentation and membrane blebbing [33–35].
Apoptosis of vascular smooth muscle cells (VSMCs) occurs in vivo under both physiological and pathological settings. Apoptosis modulators in the vasculature are numerous and complex. Candidates may include reactive oxygen species [36] NO [37], angiotensin type 2 (AT2), receptors [38] and the endothelin system [39]. Reactive oxygen species are involved in the pathogenesis of hypertension and in apoptosis of vascular cells, where, specifically, O2
– induces proliferation and H2O2 may induce apoptosis via a protein kinase C-dependent mechanism [40]. Angiotensin (Ang) II is also a potential trigger of apoptosis [38,41]. Ang II infusion in normotensive rats raised blood pressure and increased apoptotic rate in thoracic aortae by activation of angiotensin type 1 (AT1) and AT2 receptor subtypes [42].
Almost all apoptotic stimuli induce the activation of some specific proteases, called caspases, which form a whole family of different cysteine-proteases cleaving target proteins at asparagine residues. Damage to DNA or to other vital molecules propagates a cascade of reaction, which activates death programs inside the cell [43,33] via one of two pathways. The extrinsic pathway, or the death receptor pathway, is initiated by the activation of transmembrane death receptors by the binding of proteins such as CD95, tumor necrosis factor-
(TNF-), and Fas ligand. Activation of the death receptors activates the membrane proximal initiator caspase-8 (and/or caspase-10), which then cleaves procaspase-3 to generate the active effector caspase-3. The intrinsic pathway, or the mitochondrial death pathway, requires disruption of the mitochondrial membrane [e.g., by staurosporine (ST), actinomycin D, peroxide, ultraviolet (UV) radiation] and/or the release or translocation of cytochrome c (cyt-c) [44] and other apoptosis-inducing factors from the mitochondrial intermembrane space to the cytoplasm that subsequently activates cytosolic caspases and induces apoptosis. By controlling both vascular tone and apoptosis [45] mitochondria are potentially important in the etiology and therapy of vascular disease, but their role in PAH is not known (Fig. 3
).
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Fig. 3. A general model of events in apoptosis. Damage to DNA or to other vital molecules propagates a cascade of reaction, which activates death programs inside the cell, via extrinsic and intrinsic pathways. The extrinsic pathway, or the death receptor pathway, is initiated by the activation of transmembrane death receptors by the binding of proteins such as CD95, tumor necrosis factor- (TNF-), and Fas ligand. Activation of the death receptors activates the membrane proximal initiator caspase-8 (and/or caspase-10), which then cleaves procaspase-3 to generate the active effector caspase-3. Some stimuli (such as cytotoxic T cells) directly activate caspases by releasing granzymes.The intrinsic pathway, or the mitochondrial death pathway, requires disruption of the mitochondrial membrane and/or the release of cytochrome c (cyt-c) and other apoptosis-inducing factors from the mitochondrial intermembrane space to the cytoplasm that subsequently activates cytosolic caspases and induces apoptosis. Regulatory proteins of the BCL-2 family can either inhibit or promote cell death. Execution caspases (caspase-3) activate latent cytoplasmatic endonuclease and proteases that degrade cytoskeletal and nuclear proteins, which results in intracellular degradation. The end result is the formation of apoptotic bodies and consequent binding and uptaking by phagocytic cells.
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Several ion channels as well as transporters have been recently implicated to be involved and essential for apoptosis. This group described a strong efflux of potassium and sodium on induction of apoptosis by several stimuli, resulting in a strong decrease in the intracellular potassium concentration [46]. The role of K+ channels in apoptosis was proposed by the original work of Yu et al. in 1997 [47] and subsequently supported by other investigators [48–50]. Opening of sarcolemmal K+ channels increases efflux or loss of cytoplasmic K+ and induces apoptotic volume decrease (AVD), whereas closure or downregulation of K+ channels decelerates apoptotic cell shrinkage and attenuates apoptosis [48,49,51,52,47].
Cell viability is governed at the molecular level by a balance between proapoptotic and antiapoptotic signals mediated by a number of gene families, the most prominent being the Bcl-2 family. Bcl-2 family members that promote cell survival include Bcl-2, A1, and the long form of Bcl-X (Bcl-XL), whereas Bax, Bad, and Bid function to promote apoptosis. Apoptosis also require the intervention of specific sets of genes, including c-fos, c-myc, and p53-ras
[53–56]. The gene that causes familial primary pulmonary hypertension has been discovered to be bone morphogenetic protein receptor 2 (BMPR2) [57,58]. The degree of apoptosis induced by these genes is critical in mediating the in vivo responses to gene therapy and the maintenance of the crucial balance between cell death and viability.
Increased elastase activity and deposition of the matrix glycoprotein tenascin-C (TN), codistributing with proliferating smooth muscle cells (SMCs), are features of pulmonary vascular disease. In organ culture studies, changes in TN expression were associated with MMP-2 and MMP-9 activity, showing that MMP-2 activity regulates TN synthesis in cultured SMCs [59]. Inhibition of MMP-2 was associated with a reduction in TN expression and onset of apoptosis [59]. Thus, there is a functional relationship between TN and MMPs, which codistribute at sites of vascular pathology [15,16,60].
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4. Role of apoptosis in development of pulmonary vascular remodeling
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A considerable amount of information is known about the cellular and molecular mechanisms that control pulmonary vascular remodeling. Little attention has been given, however, to the mechanisms, which produce regression of pulmonary vascular remodeling. Apoptosis has important pathophysiological consequences contributing to the loss of pulmonary SMC and therefore in reversing the pulmonary pressure. Apoptosis eliminates unnecessary cells [61] such as cells migrated into the vascular lumen and hypertrophied cells accumulated in the pulmonary vasculature [8].
In recent years, the process of the programmed cell death has gained much interest because of its influence on many pathological states. Increased PASMC proliferation and decreased PASMC apoptosis can concurrently mediate thickening of the pulmonary vasculature, which subsequently reduces the inner-lumen diameter of pulmonary arteries, increases pulmonary vascular resistance, and raises PAP [8,9,21,62]. Results of many experiments suggest that apoptosis play a key role in resolution of vascular remodeling [21] and clearly show that pulmonary arteries have capacity to return to normal architecture [63]. In animal experiments, it has been demonstrated that inducing apoptosis of hypertrophied PASMC in intact pulmonary vessels can prevent the progression of the medial hypertrophy [8,63,64]. However, other data shows that, compared with PASMCs from normal subjects and patients with SPH, PASMCs from PPH patients exhibited a significant resistance to apoptotic inducers such as BMP-2, -7, and ST [65].
The balance between apoptosis and cell proliferation is vital for cellular homeostasis, yet little is known about the mechanisms that coordinate these two cell fates, particularly in the vessel wall. A recently identified class of cysteine proteases termed caspases coordinates the execution of the death program. Although apoptosis has long been recognized as a principal mechanism for the elimination of redundant, autoreactive, or neoplastic cells, it may also be a mechanism for the elimination of the ‘misguided’ proliferative PASMC in remodeled pulmonary vasculature [8] Indeed, apoptosis in hypertrophied PASMC has been attributed to regression in medial hypertrophy, whereas inhibition of apoptosis is related to progression of pulmonary vascular medial thickening [28,64,66]. Whether apoptosis is a growth-related compensatory mechanism or a primary process remains to be clarified. However, apoptotic cell death may also be regulated independently of cell growth.
Precise control of the balance of cell apoptosis and proliferation in PASMC plays a critical role in maintaining: (1) the normal structural and functional integrity of the pulmonary vasculature and (2) the low pulmonary arterial pressure in normal subjects. The role of apoptosis in the pulmonary vascular remodeling needs further research. The identification of biochemical markers of apoptosis and other methodological advances will ultimately help in understanding the role of apoptotic cell death in vascular remodeling and in treatment of hypertensive pulmonary disease.
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5. Apoptosis as a therapeutic approach for patients with pulmonary hypertension
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During the past few years we have witnessed tremendous advancements and have gained considerable insight in our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). Several of these new insights have led to the development and clinical application of novel treatments for this devastating disease. The finding that normal vascular smooth muscle cells (VSMCs), both rat and human, undergo apoptosis in culture [67] indicates that normal VSMCs possess the machinery to undergo apoptosis. Apoptosis may be one method of regulating cell number in the vessel wall.
Although heart–lung transplantation remains the only definitive treatment for patients with advanced PAH, an antiremodeling approach to PAH treatment appears to be feasible, for several reasons. First, hypertensive pulmonary artery (PA) from patients with primary pulmonary hypertension (PPH) has been demonstrated to be actively remodeled [7] and interference with remodeling has been shown to slow or reverse the progress of the disease experimentally [68]. Second, factors that are likely to promote remodeling, such as ACE, as well as possibly others, are present at the site of active remodeling [69]. Therefore, antiremodeling treatment may be a potential therapeutic option against various types of PAH.
Advanced pulmonary arterial hypertension is characterized by extensive vascular remodeling that is usually resistant to vasodilator therapy. There is now a shift in the interest of the scientific community, focusing on therapies aiming to reverse the proliferative remodeling in PAH [70]. The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension. Observations made by scientists suggest a novel strategy to treat pulmonary vascular disease by inducing regression of pulmonary vascular medial thickening, which is a pathological feature in patients with PPH and other types of severe pulmonary hypertension [8,63,64]. The remodeling of vascular structure, including the regression of vascular hypertrophy, is now considered a key therapeutic target in the effort to reduce mortality and morbidity associated with high blood pressure [71–73]. Inhibition of PASMC growth and augmentation of cell apoptosis could serve as therapeutic approaches for patients with pulmonary hypertension [74,75].
In animal models of pulmonary hypertension a variety of treatments have been used, including vasodilators [76,77] anticoagulant agents [78] and lung or heart–lung transplantation [79,80] but none have resulted in improved survival in a prospective, randomized trial. Several antihypertensive drugs currently used in therapy may exert their pharmacological effects by promoting SMC apoptosis [81]. However, it has been difficult to manipulate apoptosis in vivo, because most drugs targeting intracellular signaling events involved in apoptosis are not very well membrane permeable. Ion channels with their extracellular domain might be very attractive targets for the development of drugs preventing or inducing apoptosis, because they can be easily reached and modified in the extracellular compartment [81].
Effective therapies must promote from proliferation to apoptosis. We here summarize the relatively small number of most recent studies with different therapeutic alternatives available in the PAH by inducing apoptosis chiefly of PSMSc. We provide specific examples of how modulation of the apoptotic process contributes to pulmonary arterial medial hypertrophy regression. The sporadic promotion of apoptosis may require multiple therapeutic strategies deployed to numerous apoptotic targets.
5.1 Survivin
Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. McMurtry et al. reported that adenovirus-mediated overexpression of survivin – a multipotent inhibitor of apoptosis – induces PAH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative properties reverses established monocrotaline-induced PAH [82]. Survivin is a critical regulator of SMC apoptosis. These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies [83]. The use of molecular antagonists of survivin to increase cell death and to prevent pathological vascular remodeling might hold therapeutic potential [84].
5.2 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors: mevastatin and simvastatin
Compounds with antiproliferative effects on vascular endothelial and smooth muscle cells, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (mevastatin and simvastatin), can prevent the development of experimental hypertensive pulmonary vascular disease [85,86]. Mevastatin can both inhibit cell proliferation and induce apoptosis in PASMCs through p27Kip1-independent pathways and may be important therapeutic agents in pulmonary arterial hypertension [87].
Simvastatin attenuates monocrotaline-induced pulmonary vascular remodeling with neointimal formation, pulmonary arterial hypertension, and right ventricular hypertrophy in rats. Simvastatin increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type. Thus, simvastatin reverses pulmonary arterial neointimal formation and PAH by inducing apoptosis of neointimal smooth muscle cells [88].
5.3 Apoptosis signal-regulating kinase 1 (ASK1)
ASK1 has been identified as an apoptosis-inducing kinase [89] and recently has also reported to be implicated in a variety of cellular functions. ASK1 plays a critical role in vascular remodeling. Researches obtained the evidence that ASK1 directly participates in VSMC proliferation and migration and neointimal thickening in injured artery. Of note are the observations that gene transfer of DN-ASK1 significantly prevented neointimal hyperplasia as shown by the I/M ratio and suppressed VSMC proliferation in either the intima or the media. ASK1 may provide the basis for the development of new therapeutic strategy for vascular diseases [90].
5.4 Peroxisome proliferator-activated receptor gamma (PPARgamma)
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily, which regulates transcription of target genes in a ligand-dependent manner. Ligands for PPARgamma have been shown to attenuate proliferation of vascular smooth muscle cells, and to induce apoptosis in several cell lines in vitro. PPARgamma ligands reduce MCT-induced pulmonary hypertension and pulmonary vascular wall thickening in rats. Inhibition of MCT-induced cell proliferation and induction of apoptosis in the pulmonary arterial walls may account for this effect [91].
5.5 Bradykinin receptor agonists
Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Taraseviciene-Stewart et al. have reported that treatment of severely pulmonary hypertensive rats with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure and of right ventricular hypertrophy. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels [92].
5.6 Dichloroacetate (DCA)
Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. Dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media and decreasing proliferation. Thus mitochondria-dependent apoptosis is a potential target for therapy and DCA as an effective and selective treatment for PAH [93].
5.7 Elastase inhibitors
Administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. In pulmonary artery (PA) organ culture the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through alphavbeta3-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH. Selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH [94].
5.8 Rho/Rho-associated kinase (Rho-kinase) system
The Rho/Rho-associated kinase (Rho-kinase) system is implicated in various cellular functions, including migration, proliferation, and apoptosis. Specific Rho-kinase inhibitor, Y27632, inhibited early neointimal lesion formation, by suppressing early SMC migration into the intima and prevented neointima formation in the later phase by enhancing neointimal SMC apoptosis [95]. Kohtaro Abe et al. found that long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction [96].
These findings indicated that the Rho-kinase-mediated pathway is substantially involved in the MCT-induced PH and that the long-term inhibition of Rho-kinase prevents or even causes a marked improvement of the MCT-induced PH through multiple mechanisms, including: (1) inhibition of VSMC proliferation with enhanced apoptosis, (2) reduced macrophage infiltration, and (3) improvement of endothelium-dependent relaxation and VSMC hypercontraction.
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6. Conclusions
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Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. The net balance between proliferation and apoptosis determines the extent of SMC growth. Taken together shown in this study, we speculate that inhibition of apoptosis in PASMCs is involved in the development and progression of pulmonary arterial medial hypertrophy, whereas induction or enhancement of PASMC apoptosis may be targeted to develop therapeutic approaches for pulmonary vascular remodeling in patients with PAH. SMC apoptosis may be a selective target for pharmacological intervention in hypertension. Understanding the apoptotic process, which appears as complex and highly regulated as that of proliferation, may yield valuable information in treatment of these diseases. An alteration in thresholds for apoptosis is becoming prominent concepts as we move along in our quest to understand and ultimately treat this disease.
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Footnotes
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1 Tel.: +86 85726093. 
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References
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|---|
- Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward Ken, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-ß family. J Med Genet 2000;37:741-745.[Abstract/Free Full Text]
- Bailey CL, Channick RN, Rubin LJ. A new era in the treatment of primary pulmonary hypertension. Heart 2001;85(3):251-252.[Free Full Text]
- D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349.[Abstract/Free Full Text]
- Rubin LJ. Primary pulmonary hypertension. Chest 1993;104:236-250.[CrossRef][Medline]
- Intengan HD, Schiffrin EL. Roles of apoptosis, inflammation, and fibrosis. Hypertension 2001;38:581.[Abstract/Free Full Text]
- Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension 1996:505-506.
- Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research ‘work in progress’. Circulation 2000;102:2781-2791.[Abstract/Free Full Text]
- Rabinovitch M. Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 1998;114:213S-224S.[Medline]
- Stenmark KR, Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 1997;59:89-144.[CrossRef][Medline]
- Zhu L, Wigle D, Hinek A, Kobayashi J, Ye C, Zuker M, Dodo H, Keeley FW, Rabinovitch M. The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin. J Clin Invest 1994;94:1163-1171.[Medline]
- Thompson K, Kobayashi J, Childs T, Wigle D, Rabinovitch M. Endothelial and serum factors which include apolipoprotein A1 tether elastin to smooth muscle cells inducing serine elastase activity via tyrosine kinase-mediated transcription and translation. J Cell Physiol 1998;174:78-89.[CrossRef][Medline]
- Todorovich-Hunter L, Johnson DJ, Ranger P, Keeley FW, Rabinovitch M. Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline: a biochemical and ultrastructural study. Lab Invest 1988;58:184-195.[Medline]
- Prosser I, Stenmark K, Suthar M, Crouch E, Mecham R, Parks W. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol 1989;135:1073-1088.[Abstract]
- Botney MD, Kaiser LR, Cooper JD, Mecham RP, Parghi D, Roby J, Parks WC. Extracellular matrix gene expression in atherosclerotic hypertensive pulmonary arteries. Am J Pathol 1992;140:357-364.[Abstract]
- Jones PL, Cowan K, Rabinovitch M. Tenascin-C, proliferation and subendothelial accumulation of fibronectin in progressive pulmonary vascular disease. Am J Pathol 1997;150:1349-1360.[Abstract]
- Jones PL, Rabinovitch M. Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 1996;79:1131-1142.[Abstract/Free Full Text]
- Smith P, Heath D. Ultrastructure of hypoxia hypertensive pulmonary vascular disease. J Pathol 1976;121:93-101.[CrossRef]
- Tucker A, McMurtry II, Reeves JT, Alexander AF, Will DHH, Grover RF. Lung vascular smooth muscle as a determinate of pulmonary hypertension at high altitude. Am J Physiol 1975;228:762-767.[Abstract/Free Full Text]
- Grover RF, Vogel JK, Averill KH, Blount SG. Pulmonary hypertension: individual and species variability relative to vascular reactivity. Am Heart J 1963;66:1-3.[CrossRef][Medline]
- Mulvany MJ. Small artery remodeling and significance in the development of hypertension. News Physiol Sci 2002:105-109.
- Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 1994;330:1431-1438.[Free Full Text]
- Tuttle JL, Nachreiner RD, Bhuller AS, Condict KW, Connors BA, Herring BP, Dalsing MC, Unthank JL. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression. Am J Physiol Heart Circ Physiol 2001;281:H1380-H1389.[Abstract/Free Full Text]
- Rizzoni D, Porteri E, Boari GEM, De Ciuceis C, Sleiman I, Lorenza Muiesan M, Castellano M, Miclini M, Agabiti-Rosei E. Prognostic significance of small-artery structure in hypertension. Circulation 2003;108:2230.[Abstract/Free Full Text]
- Pries AR, Secomb TW, Gaehtgens P. Structural autoregulation of terminal vascular beds. Vascular adaptation and development of hypertension. Hypertension 1999;33:153-161.[Abstract/Free Full Text]
- Naeije R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Am Thorac Soc 2005;2:20-22.
- Lerman A, Cannan CR, Higano SH, Nishimura RA, Holmes Jr. DR. Coronary vascular remodeling in association with endothelial dysfunction. Am J Cardiol 1998;81:1105-1109.[CrossRef][Medline]
- Welsh CH, Hassell KL, Badesch DB, Kressin DC, Marlar RA. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996;110:710-717.[CrossRef][Medline]
- Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 1995;9:183-189.[Abstract]
- Haunstetter A, Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res 1998;82:1111-1129.[Free Full Text]
- Riley DJ, Thakker-Varia S, Wilson FJ, Poiani GJ, Tozzi CA. Role of proteolysis and apoptosis in regression of pulmonary vascular remodeling. Physiol Res 2000;49:577-585.[Medline]
- Nagata S, Golstein P. The Fas death factor. Science 1995;267:1449-1456.[Abstract/Free Full Text]
- Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995;267:1456-1462.[Abstract/Free Full Text]
- Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770-776.[CrossRef][Medline]
- Zimmermann KC, Bonzon C, Green DR. The machinery of programmed cell death. Pharmacol Ther 2001;92:57-70.[CrossRef][Medline]
- Okada Y, Maeno E, Shimizu T, Dezaki K, Wang J, Morishima S. Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J Physiol 2001;532:3-16.[Abstract/Free Full Text]
- Irani K. Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 2000;87:179-183.[Abstract/Free Full Text]
- Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis: countervailing influences of nitric oxide and angiotensin II. Circ Res 1996;79:748-756.[Abstract/Free Full Text]
- Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 1996;93:156-160.[Abstract/Free Full Text]
- Cattaruzza M, Dimigen C, Ehrenreich H, Hecker M. Stretch-induced endothelin B receptor–mediated apoptosis in vascular smooth muscle cells. FASEB J 2000;14:991-998.[Abstract/Free Full Text]
- Li PF, Maasch C, Haller H, Dietz R, von Harsdorf R. Requirement for protein kinase C in reactive oxygen species-included apoptosis of vascular smooth muscle cells. Circulation 1999;100:967-973.[Abstract/Free Full Text]
- Tea BS, Der Sarkissian S, Touyz RM, Hamet P, deBlois D. Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. Hypertension 2000;35:1069-1073.[Abstract/Free Full Text]
- Diep QN, Li JS, Schiffrin EL. In vivo study of AT1 and AT2 angiotensin receptors in apoptosis of rat blood vessels. Hypertension 1999;34:617-624.[Abstract/Free Full Text]
- Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999;68:383-424.[CrossRef][Medline]
- Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome C from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997;275:1132-1136.[Abstract/Free Full Text]
- Duchen MR. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J Physiol 1999;516:1-17.[Abstract/Free Full Text]
- Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 1999;79:1127-1155.[Abstract/Free Full Text]
- Yu SP, Yeh C-H, Sensi SL, Gwag BJ, Canzoniero LMT, Farhangrazi ZS, Ying HS, Tian M, Dugan LL, Choi DW. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 1997;278:114-117.[Abstract/Free Full Text]
- Bortner CD, Hughes Jr. FM, Cidlowski JA. A primary role for K+ and Na+ efflux in the activation of apoptosis. J Biol Chem. 1997;272:32436-32442.[Abstract/Free Full Text]
- Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JX-J. Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol Cell Physiol 2001;280:C970-C979.[Abstract/Free Full Text]
- Vu CCQ, Bortner CD, Cidlowski JA. Differential involvement of initiator caspases in apoptotic volume decrease and potassium efflux during Fas- and UV-induced cell death. J Biol Chem 2001;276:37602-37611.[Abstract/Free Full Text]
- Nietsch HH, Roe MW, Fiekers JF, Moore AL, Lidofsky SD. Activation of potassium and chloride channels by tumor necrosis factor . Role in liver cell death. J Biol Chem 2000;275:20556-20561.[Abstract/Free Full Text]
- Trimarchi JR, Liu L, Smith PJS, Keefe DL. Apoptosis recruits two-pore domain potassium channels used for homeostatic volume regulation. Am J Physiol Cell Physiol 2002;282:C588-C594.[Abstract/Free Full Text]
- Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993;75:241-251.[CrossRef][Medline]
- Smeyne RJ, Vendrell M, Hayward M, Baker SJ, Miao GG, Schilling K, Robertson LM, Curran T, Morgan JI. Continuous c-fos expression precedes programmed cell death in vivo
. Nature 1993;363:166-169.[CrossRef][Medline]
- Lane DP. p53, guardian of the genome. Nature 1993;358:15-16.
- Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993;362:849-852.[CrossRef][Medline]
- The International PPH ConsortiumLane KB, Machado VC, Pauciulo MW, Thomson JR, Phillips III JA, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000;26:81-84.[CrossRef][Medline]
- Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Ficsher SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-744.[CrossRef][Medline]
- Jones PL, Crack J, Rabinovitch M. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the avb3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 1997;139:279-293.[Abstract/Free Full Text]
- Patel MI, Melrose J, Ghosh P, Appleberg M. Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. J Vasc Surg 1996;24:82-92.[CrossRef][Medline]
- Uhal BD. Apoptosis in lung fibrosis and repair. Chest 2002;122(Suppl 6):293S-298S.[CrossRef][Medline]
- Voelkel NF, Tuder RM. Cellular and molecular biology of vascular smooth muscle cells in pulmonary hypertension. Pul Pharmacol Ther 1997;10:231-241.[CrossRef][Medline]
- Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000;6:698-702.[CrossRef][Medline]
- Cowan KN, Jones PL, Rabinovitch M. Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. Circ Res 1999;84:1223-1233.[Abstract/Free Full Text]
- Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX-J. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L740-L754.[Abstract/Free Full Text]
- Durmowicz AG, Stenmark KR. Mechanisms of structure remodeling in chronic pulmonary hypertension. Pediatr Rev (online) 1999;20:e91-e102.
- Bjorkerud S, Bjorkerud B, Joelsson M. Structural organization of reconstituted human arterial smooth muscle tissue. Arterioscler Thromb 1994;14:644-651.[Abstract/Free Full Text]
- Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000;105:21-34.[Medline]
- Qing F, McCarthy TJ, Markham J, Schuster DP. Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans: a positron emission tomography study. Am J Respir Crit Care Med 2000;161:2019-2025.[Abstract/Free Full Text]
- Rubin LJ. Therapy of pulmonary hypertension: the evolution from vasodilators to antiproliferative agents. Am J Respir Crit Care Med 2002;166:1308-1309.[Free Full Text]
- Mulvany MJ. Determinants of vascular structure. J Cardiovasc Pharmacol 1992;19(Suppl 5):S1-S6.[CrossRef]
- Mulvany MJ. The development and regression of vascular hypertrophy. J Cardiovasc Pharmacol 1992;19(Suppl 2):S22-S27.[Medline]
- Safar ME, Levy BI, London GM. Arterial structure in hypertension and the effects of angiotensin converting enzyme inhibition. J Hypertens Suppl 1992;10:S51-S57Review.[Medline]
- Dispersyn G, Nuydens R, Connors R, Borgers M, Geerts H. Bcl-2 protects against FCCP-induced apoptosis and mitochondrial membrane potential depolarization in PC 12 cells. Biochim Biophys Acta 1999;1428:357-371.[Medline]
- Fernández-Salas E, Sagar M, Cheng C, Yuspa SH, Weinberg WC. p53 and tumor necrosis factor regulate the expression of a mitochondrial chloride channel protein. J Biol Chem 1999;274:36488-36497.[Abstract/Free Full Text]
- Weir EK, Rubin LJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Elliott CG, Fishman AP, Goldring RM, Groves BM. The acute administration of vasodilators in primary pulmonary hypertension: experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension. Am Rev Respir Dis 1989;140:1623-1630.[Medline]
- Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81.[Abstract]
- Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon, MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984;70:580-587.[Abstract/Free Full Text]
- Pasque MK, Trulock EP, Kaiser LR, Cooper JD. Single-lung transplantation for pulmonary hypertension: three-month hemodynamic follow-up. Circulation 1991;84:2275-2279.[Abstract/Free Full Text]
- Glanville AR, Burke CM, Theodore J, Robin ED. Primary pulmonary hypertension: length of survival in patients referred for heart-lung transplantation. Chest 1987;91:675-681.[CrossRef][Medline]
- Smith P, Heath D. Ultrastructure of hypoxia hypertensive pulmonary vascular disease. J Pathol 1976;121:93-101.[CrossRef]
- McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectivity induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115:1479-1491. doi: 10.1172/JCI23203.[CrossRef][Medline]
- Blanc-Brude OP, Yu J, Simosa H, Conte MS, Sessa WC, Altieri DC. Inhibitor of apoptosis protein survivin regulates vascular injury. Nat Med 2002;8:987-994.[CrossRef][Medline]
- Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003;3:46-54.[CrossRef][Medline]
- Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation preventing rho GTPase-inducec down-regulation of p27Kip 1
. J Biol Chem 1999;274:21926-21931.[Abstract/Free Full Text]
- Indolfi C, Cioppa A, Stabile E, Di Lorenzo E, Esposito G, Pisani A, Leccia A, Cavuto L, Stingtone AM, Chieffo A, Capozzolo C, Chiariello M. Effects of hydroxymethylglutaryl coenzyme A reducates inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol 2000;35:214-221.[Abstract/Free Full Text]
- Fouty BW, Rodman DM. Mevastatin Can Cause G1 Arrest and Induce Apoptosis in Pulmonary Artery Smooth Muscle Cells Through a p27Kip1-Independent Pathway. Circ Res 2003;92(5):501-509.[Abstract/Free Full Text]
- Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, Qiu D, Benson G, Pearl RG, Kao PN. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108:1640.[Abstract/Free Full Text]
- Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 1998;281:1860-1863.[Abstract/Free Full Text]
- Izumi Y, Kim S, Yoshiyama M, Izumiya Y, Yoshida K, Matsuzawa A, Koyama H, Nishizawa Y, Ichijo H, Yoshikawa J, Iwao H. Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia. Circulation 2003;108:2812.[Abstract/Free Full Text]
- Matsuda Y, Hoshikawa Y, Ameshima S, Suzuki S, Okada Y, Tabata T, Sugawara T, Matsumura Y, Kondo T. Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats. Nihon Kokyuki Gakkai Zasshi 2005;43(5):283-288.[Medline]
- Taraseviciene-Stewart L, Scerbavicus R, Stewart JM, Gera L, Demura Y, Cool C, Kasper M, Voelkel NF. Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy. Peptides 2005;26(8):1292-1300.[CrossRef][Medline]
- Sean McMurtry M, Bonnet S, Wu X, Dyck JRB, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circulation 2004;95:830.
- Merklinger SL, Jones PL, Martinz EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005;112(3):423-431.[Abstract/Free Full Text]
- Shibata R, Kai H, Seki Y, Kato S, Morimatsu M, Kaibuchi K, Imaizumi T. Role of rho-associated kinase in neointima formation after vascular injury. Circulation 2001;103:284.[Abstract/Free Full Text]
- Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshita A. Long-term treatment with a rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circulation 2004;94:385.
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Abstract
1. Pulmonary artery hypertension...
