Purdham Daniel M, Rajapurohitam Venkatesh, Zeidan Asad, Huang Cathy, Gross Garrett J, Karmazyn Morris
Dept. of Physiology and Pharmacology, Univ. of Western Ontario, London, ON, N6A 5C1, Canada.
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H441-6. doi: 10.1152/ajpheart.91537.2007. Epub 2008 May 9.
The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.
16 kDa的脂肪因子瘦素已被证明对培养的心肌细胞具有直接的肥大作用，尽管其作为心肌梗死后重塑和心力衰竭内源性因素的作用尚未确定。因此，我们研究了体内瘦素受体阻断对冠状动脉结扎（CAL）后血流动力学功能和心肌肥大的影响。在存在和不存在瘦素受体抗体的情况下，对接受左主冠状动脉结扎7天或28天的大鼠测量心脏功能和生化参数。接受相同处理但未结扎动脉的动物作为假手术对照。CAL导致心肌肥大，在心肌梗死后28天最为明显，表现为左心室重量与体重比增加和心房利钠肽基因表达增加，而瘦素受体拮抗作用可消除这两者。瘦素受体阻断还显著改善了左心室收缩功能，减轻了左心室舒张末期压力的升高，并降低了CAL后28天与细胞外基质重塑相关基因的表达。总之，瘦素受体中和抗体改善心脏功能的能力证明内源性瘦素在CAL后导致心肌肥大。靶向心肌瘦素受体有可能是减轻心肌梗死后重塑的一种可行且新颖的方法。
