Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice
Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice
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DOI：
10.1677/joe.1.06241
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Ren, J
中科院分区：
文献类型：
--
作者：
Dong, F;Zhang, X;Ren, J
肥胖基因产物瘦素的水平通常与体重正相关，支持高瘦素血症导致肥胖相关性心功能障碍的观点。然而，瘦素水平和心脏功能之间的联系尚未阐明。本研究旨在探讨瘦素缺乏（由瘦素基因点突变引起）在心肌细胞收缩功能中的作用。机械性能和细胞内Ca 2+瞬变进行了评价，在心室肌细胞瘦控制和瘦素缺乏ob/ob肥胖小鼠在12周龄。透射电镜观察心肌超微结构。ob/ob小鼠明显肥胖、高胰岛素血症、高血糖、低瘦素血症和血糖正常。超微结构检查显示ob/ob小鼠心室组织线粒体肿胀、嵴排列紊乱。肥胖/肥胖小鼠的心肌细胞显示瘦素受体Ob-R的表达减少，横截面积更大，缩短峰值和最大缩短/再长速度降低，再长时间延长，但不缩短持续时间。与机械特性一致，ob/ob小鼠的肌细胞在电刺激后表现出细胞内Ca 2+释放减少，细胞内Ca 2+衰减速率减慢。有趣的是，在ob/ob心肌细胞中观察到的收缩畸变被体外瘦素孵育显著改善。在年龄和性别匹配的高脂肪诱导的肥胖小鼠中未观察到收缩功能障碍。这些结果表明，瘦素缺乏有助于心脏收缩功能障碍，其特征在于收缩和舒张功能障碍，受损的细胞内Ca 2+止血和超微结构紊乱的心室肌细胞。
The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesity-associated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca2+ transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca2+ release upon electrical stimulus associated with a slowed intracellular Ca2+ decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age- and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca2+ hemostasis and ultrastructural derangement in ventricular myocytes.