du Toit E F, Nabben M, Lochner A
Department of Medical Physiology, Faculty of Health Sciences, University of Stellenbosch, 19063, Tygerberg 7505, South Africa.
Basic Res Cardiol. 2005 Jul;100(4):346-54. doi: 10.1007/s00395-005-0528-5. Epub 2005 Apr 14.
The mechanisms for obesity induced myocardial remodelling and subsequent mechanical dysfunction are poorly understood. There is good evidence that angiotensin II and TNFalpha have strong growth promoting properties and are elevated with obesity. In addition, these two peptides may interact to exacerbate myocardial ischaemic/reperfusion injury.
Obesity increases systemic and myocardial renin-angiotensin system (RAS) activity and TNFalpha levels and contributes to obesity induced cardiac remodelling and ischaemic/reperfusion injury.
Male Wistar rats were placed on a standard rat chow diet or cafeteria diet for 16 weeks. Two additional groups of rats received the respective diets and losartan (30 mg/ kg/d) in their drinking water. Hearts were perfused on the isolated working rat heart perfusion system and mechanical function was documented before and after 15 min normothermic total global ischaemia. Blood and myocardial samples were collected for angiotensin II, TNFalpha and NADPH oxidase activity determinations.
The rats on the cafeteria diet became obese compared to rats on the standard rat chow (438 +/- 5.9 g vs 393 +/- 7.3 g for control, p < 0.05). Obesity was associated with elevated serum angiotensin II (0.050 +/- 0.015 pmol/ml vs. 0.035 +/- 0.003 pmol/ml, p < 0.05) and TNFalpha levels (42.8 +/- 5.93 pg/ml vs. 13.18 +/- 2.50 pg/ml, p < 0.05), and increased heart to body weight ratios (3.1 +/- 0.04 mg/g vs. 2.8 +/- 0.03 mg/g, p < 0.05). Losartan had no effect on body weight but decreased basal myocardial angiotensin II and TNFAlpha levels as well as heart to body weight ratio in the obese and lean controls (2.5 +/- 0.05 mg/g and 2.6 +/- 0.04 mg/g relative to their controls, p < 0.05). Hearts from obese rats had lower reperfusion aortic outputs (AO) than their concurrent controls (18.42 +/- 1.17 ml/min vs. 27.8 +/- 0.83 ml/min, p < 0.05). Losartan improved aortic output recoveries in obese rats (23.0 +/- 1.71 ml/min, p < 0.05).
Obesity increased serum angiotensin II and TNFalpha levels, blood pressure, and heart weight to body weight ratios. These changes were associated with decreased basal and post-ischaemic myocardial mechanical function. Chronic AT(1) receptor antagonism prevented the adverse changes in heart weight, mechanical function and susceptibility to ischaemic/reperfusion injury. Although current data do not exclude additional mechanisms for obesity induced cardiac remodelling, they suggest that angiotensin II may contribute to obesity induced cardiac remodelling and ischaemic/reperfusion injury.
肥胖所致心肌重塑及随后出现的机械功能障碍的机制尚不清楚。有充分证据表明，血管紧张素II和肿瘤坏死因子α具有强大的促生长特性，且在肥胖时升高。此外，这两种肽可能相互作用，加剧心肌缺血/再灌注损伤。
肥胖会增加全身及心肌肾素-血管紧张素系统（RAS）活性和肿瘤坏死因子α水平，并导致肥胖引起的心脏重塑及缺血/再灌注损伤。
将雄性Wistar大鼠分为两组，分别给予标准大鼠饲料或自助餐式饮食，持续16周。另外两组大鼠在饮用的水中加入相应饮食及氯沙坦（30毫克/千克/天）。在离体工作大鼠心脏灌注系统上对心脏进行灌注，并记录15分钟常温全心缺血前后的机械功能。采集血液和心肌样本，测定血管紧张素II、肿瘤坏死因子α及NADPH氧化酶活性。
与给予标准大鼠饲料的大鼠相比，给予自助餐式饮食的大鼠变得肥胖（对照组体重为393±7.3克，给予自助餐式饮食的大鼠体重为438±5.9克，p<0.05）。肥胖与血清血管紧张素II水平升高（0.050±0.015皮摩尔/毫升对0.035±0.003皮摩尔/毫升，p<0.05）、肿瘤坏死因子α水平升高（42.8±5.93皮克/毫升对13.18±2.50皮克/毫升，p<0.05）以及心脏与体重比值增加（3.1±0.04毫克/克对2.8±0.03毫克/克，p<0.05）相关。氯沙坦对体重无影响，但降低了肥胖和瘦对照组的基础心肌血管紧张素II和肿瘤坏死因子α水平以及心脏与体重比值（相对于各自对照组分别为2.5±0.05毫克/克和2.6±0.04毫克/克，p<0.05）。肥胖大鼠心脏的再灌注主动脉输出量（AO）低于同期对照组（18.42±1.17毫升/分钟对27.8±0.83毫升/分钟，p<0.05）。氯沙坦改善了肥胖大鼠的主动脉输出量恢复情况（23.0±1.71毫升/分钟，p<0.05）。
肥胖会增加血清血管紧张素II和肿瘤坏死因子α水平、血压以及心脏重量与体重比值。这些变化与基础及缺血后心肌机械功能降低有关。慢性AT(1)受体拮抗可预防心脏重量、机械功能及缺血/再灌注损伤易感性的不良变化。虽然目前的数据不排除肥胖引起心脏重塑的其他机制，但提示血管紧张素II可能参与肥胖引起的心脏重塑及缺血/再灌注损伤。
