背景:未矫正的肥胖会导致过早衰老和心血管异常。这项研究探讨了肥胖和衰老对心脏重塑和收缩功能的相互作用。
方法:心脏超声心动图几何,函数,形态学,细胞内Ca2+处理,氧化应激(DHE荧光),在年轻(3个月)和老年(12和18个月)瘦和瘦素缺乏的ob/ob肥胖小鼠中评估了STAT3和应激信号传导。在评估机械和生化特性之前,将年轻和老年瘦肉和ob/ob小鼠的心肌细胞用瘦素(1nM)在体外处理4小时。高脂肪饮食(来自脂肪的45%卡路里)和瘦蛋白受体突变体db/db肥胖小鼠在年轻和老年时进行评估以进行比较。
结果:我们的结果显示ob/ob小鼠的存活率降低。肥胖,但不太可能年龄较大的超声心动图,几何,心肌细胞功能和细胞内Ca2+特性,O2-和p47phoxNADPH氧化酶水平升高,年龄较大时几何变化更明显。免疫印迹分析显示p47phoxNADPH氧化酶升高和STAT3磷酸化减弱,在老年ob/ob小鼠中反应更明显,瘦素恢复了效果。肥胖和衰老抑制Akt的磷酸化,eNOS,AMPK,和p38,同时促进JNK和IκB的磷酸化。瘦素调节心肌细胞功能障碍,O2-产量,p47phox上调,在ob/ob小鼠中STAT3去磷酸化和应激信号传导,尽管其对应激信号传导级联的作用在老年时丧失。高脂饮食诱导的和db/db肥胖表现出与衰老相关的心肌细胞异常,尽管瘦素反应丧失,但仍让人联想到ob/ob模型。
结论:我们的数据表明,由于Akt的磷酸化,心脏重塑和收缩功能障碍中与年龄相关的肥胖反应不同,eNOS与应激信号相关的氧化应激。
Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function.
Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison.
Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2- and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2- yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response.
Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress.