Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
J Mol Med (Berl). 2010 Oct;88(10):993-1001. doi: 10.1007/s00109-010-0663-9. Epub 2010 Aug 20.
The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin-angiotensin-aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.
代谢综合征是一组代谢紊乱的病症，包括肥胖、高血压和胰岛素抵抗，这些都是糖尿病、高血压、心血管和肾脏疾病发展的危险因素。导致代谢综合征发生的病理生理异常包括线粒体氧化磷酸化和线粒体生物发生受损、胰岛素代谢信号减弱、内皮功能障碍以及相关的心肌功能异常。最近的证据表明，受损的心肌线粒体生物发生、脂肪酸代谢和抗氧化防御机制导致心脏底物灵活性降低、心脏能量效率降低和舒张功能障碍。此外，肾素-血管紧张素-醛固酮系统的增强激活以及相关的氧化应激增加可导致线粒体凋亡和降解、生物能量改变以及心脏脂质堆积。除了代谢信号和氧化应激受损外，遗传和环境因素、衰老和高血糖也会导致线粒体生物发生减少和功能障碍。这些线粒体异常可能导致以舒张功能障碍为特征的代谢性心肌病。线粒体功能障碍以及骨骼肌、肝脏和胰腺中脂质的积累也会阻碍胰岛素代谢信号和葡萄糖代谢，最终导致线粒体功能障碍进一步加重。改善线粒体功能的干预措施已被证明可以纠正胰岛素代谢信号和其他代谢和心血管异常。本文探讨了线粒体功能障碍的机制，重点关注代谢性心脏病病理生理学中氧化磷酸化和线粒体生物发生受损。
