Minakawa Masahito, Takeuchi Koh, Ito Kazuo, Tsushima Takao, Fukui Kozo, Takaya Shunichi, Fukuda Ikuo
First Department of Surgery, Hirosaki University School of Medicine, Aomori Prefecture, Hirosaki, Japan.
Eur J Cardiothorac Surg. 2003 Oct;24(4):493-501. doi: 10.1016/s1010-7940(03)00410-x.
In heart failure, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) activity is decreased, resulting in abnormal Ca(2+) 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.
Hypertrophied rat heart was created by abdominal aortic banding for 16 and 26 weeks. Then 20-40 microg/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 micromol/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.
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.
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.
在心力衰竭中，肌浆网Ca(2 +)-ATP酶（SERCA2）活性降低，导致Ca(2 +)处理异常和收缩功能障碍。我们之前报道过葡萄糖转运蛋白（GLUT4）活性受损是压力超负荷肥大心脏中心力衰竭进展的早期指标。本研究旨在探讨SERCA2和葡萄糖代谢在压力超负荷肥大心脏中的作用。还对已知可恢复GLUT4和/或SERCA2功能的甲状腺激素进行了检测。
通过腹主动脉缩窄16周和26周建立肥大大鼠心脏模型。在最后4周，每天皮下注射20 - 40μg/kg的3,5,3'-三碘-L-甲状腺原氨酸（T3）。用2μmol/L异丙肾上腺素刺激H9c2(2 - 1)大鼠心肌成肌细胞3天、7天和10天，建立肥大心肌细胞模型。在Langendorff灌注下测量肥大大鼠心脏的左心室功能。通过Western免疫印迹分析两种模型中心肌GLUT4和SERCA2的蛋白水平。酶法测定心肌细胞培养基中的葡萄糖和乳酸浓度，以确定糖酵解效率。
16周龄心脏的舒张功能（tau）显著恶化，SERCA2蛋白水平比对照组显著降低（89.3%）。在26周龄心脏中，收缩和舒张功能（+dP/dt max、-dP/dt max和tau）均显著恶化。这与GLUT4和SERCA2蛋白显著降低有关（分别为84.8%和91.6%）。在培养的肥大心肌细胞中，肥大进展过程中糖酵解从有氧转变为无氧。GLUT4蛋白在第7天显著降低（为对照组的45.6%）。这导致第10天SERCA2蛋白下调（为对照组的51.8%）。尽管T3治疗对GLUT4没有影响，但SERCA2蛋白水平几乎恢复正常，心肌功能部分改善。
我们得出结论，在早期心力衰竭中可观察到葡萄糖代谢和SERCA2功能均受损。甲状腺激素部分改善了肥大大鼠心脏的心肌功能，成功提高了SERCA2蛋白水平，但对GLUT4蛋白表达没有影响。恢复葡萄糖代谢是避免心力衰竭进一步进展的关键步骤。
