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Eur J Cardiothorac Surg 2003;24:493-501
© 2003 Elsevier Science NL

Restoration of sarcoplasmic reticulum protein level by thyroid hormone contributes to partial improvement of myocardial function, but not to glucose metabolism in an early failing heart

First Department of Surgery, Hirosaki University School of Medicine, Aomori Prefecture, Hirosaki, Japan

Received 8 August 2002; received in revised form 1 June 2003; accepted 16 June 2003.

^* Corresponding author
e-mail: ikuofuku{at}cc.hirosaki-u.ac.jp

Objective: In heart failure, sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2) activity is decreased, resulting in abnormal Ca²⁺ handling and contractile dysfunction. We have previously reported that impaired glucose transporter (GLUT4) activity was an early indicator of progression of heart failure in pressure overload hypertrophied heart. This study was aimed to examine the contribution of both SERCA2 and glucose metabolism in pressure overload hypertrophied heart. Thyroid hormone, which is known to restore GLUT4 and/or SERCA2 function, was also tested. Methods: Hypertrophied rat heart was created by abdominal aortic banding for 16 and 26 weeks. Then 20–40 µg/kg of 3,5,3'-triiodo-L-thyronine (T3) was administered subcutaneously daily for the last 4 weeks. Hypertrophied myocytes were created by the stimulation of H9c2(2-1) rat heart myoblasts with 2 µmol/L of isoproterenol for 3, 7 and 10 days. Left ventricle function of the hypertrophied rat hearts were measured in Langendorff perfusion. Myocardial protein levels of GLUT4 and SERCA2 in two models were analyzed by Western immunoblotting. Glucose and lactate concentration of cultured medium of myocytes were measured enzymatically to determine the efficacy of glycolysis. Results: Diastolic function (tau) was significantly deteriorated in 16-week heart with significantly lower SERCA2 protein (89.3%) than control. In 26-week heart, both systolic and diastolic function (+dP/dt max, -dP/dt max and tau) was significantly deteriorated. This was associated with significant decrease in both GLUT4 and SERCA2 protein (84.8 and 91.6%, respectively). In cultured hypertrophied myocytes, glycolysis was shifted from aerobic to anaerobic during progression of hypertrophy. GLUT4 protein was significantly decreased at day 7 (45.6% of control). This led to a down-regulation of SERCA2 protein at day 10 (51.8% of control). Although there was no impact of T3 treatment on GLUT4, SERCA2 protein level was almost reversed with partial improvement of myocardial function. Conclusions: We conclude that impairment of both glucose metabolism and SERCA2 function were seen in an early heart failure. Thyroid hormone partially improved myocardial function with successful improvement of SERCA2 protein but no impact on GLUT4 protein expression in hypertrophied rat heart. Restoration of glucose metabolism is a critical step to avoid further progression of heart failure.

Key Words: Myocardial hypertrophy • Glucose transporter • SR Ca²⁺-ATPase • Glycolysis • Thyroid hormone

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