Yoshikawa Yoshiro, Takaki Miyako
Department of Surgery III, Nara Medical University, Kashihara, Japan.
Nihon Yakurigaku Zasshi. 2004 Feb;123(2):77-86. doi: 10.1254/fpj.123.77.
We investigated left ventricular (LV) mechanoenergetics in acute and chronic failing hearts, induced by high Ca(2+), ischemic-reperfusion injury, diabetes mellitus (DM), and hypothyroidism, using cross-circulated excised rat heart preparations. After high Ca(2+) or ischemic-reperfusion, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat (VO(2)) and systolic pressure-volume area (PVA). This result indicated a decrease in VO(2) for total Ca(2+) handling in E-C coupling. We found proteolysis of a cytoskeletal protein, alpha-fodrin. A calpain inhibitor significantly suppressed contractile failure, decreased VO(2) for total Ca(2+) handling, and membrane alpha-fodrin degradation. In DM, the LV relaxation rate was significantly slower, resulting in the decreased O(2) consumption per min for total Ca(2+) handling in E-C coupling. In hypothyroidism, there were systolic and diastolic failures associated with the decreased O(2) consumption per beat for total Ca(2+) handling in E-C coupling. The protein level of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) was significantly lower in DM and hypothyroidism. We conclude that suppression of O(2) consumption for total Ca(2+) handling, mainly utilized by SERCA2, is a major cause of failing hearts, mediated through degradation of membrane alpha-fodrin via activation of calpain or suppressed expression of SERCA2.
我们使用交叉循环的离体大鼠心脏标本，研究了由高钙、缺血再灌注损伤、糖尿病（DM）和甲状腺功能减退引起的急性和慢性衰竭心脏的左心室（LV）机械能量学。在高钙或缺血再灌注后，出现了收缩功能衰竭，同时每搏心肌氧耗量（VO(2)）与收缩压-容积面积（PVA）之间的线性关系平行向下移位。这一结果表明在兴奋-收缩偶联中用于总钙处理的VO(2)降低。我们发现一种细胞骨架蛋白α-血影蛋白发生了蛋白水解。一种钙蛋白酶抑制剂显著抑制了收缩功能衰竭，降低了用于总钙处理的VO(2)，并减少了膜α-血影蛋白的降解。在糖尿病中，左心室舒张速率明显减慢，导致兴奋-收缩偶联中用于总钙处理的每分钟氧耗量降低。在甲状腺功能减退中，存在收缩和舒张功能衰竭，与兴奋-收缩偶联中用于总钙处理的每搏氧耗量降低有关。糖尿病和甲状腺功能减退时肌浆网钙ATP酶（SERCA2）的蛋白水平显著降低。我们得出结论，抑制主要由SERCA2利用的用于总钙处理的氧耗量，是衰竭心脏的主要原因，其通过钙蛋白酶激活介导的膜α-血影蛋白降解或SERCA2表达受抑制来实现。
