Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia
Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia
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DOI：
10.2174/157016108783955301
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发表时间：
2008-04-01
影响因子：
4.5
通讯作者：
Tyagi, Suresh C.
中科院分区：
文献类型：
--
作者：
Moshal, Karni S.;Metreveli, Naira;Tyagi, Suresh C.
慢性容量/压力超负荷诱导的心力衰竭增加氧化应激并激活基质金属蛋白酶，其导致内皮细胞-心肌细胞（EM）解偶联，最终导致心肌收缩和舒张功能下降。同型半胱氨酸（Hcy）水平升高、高同型半胱氨酸血症（HHcy）与心脏功能下降相关。同型半胱氨酸损害与诱导心室肥大相关的EM功能，导致心脏僵硬和舒张性心力衰竭。Hcy诱导的神经功能缺损由NMDA-R（N-甲基-D-天冬氨酸（NMDA）受体）激活介导。NMDA-R在心脏中表达。然而，NMDA-R在HHcy期间对心功能的作用仍处于起步阶段。NMDA-R的阻断减弱了NMDA激动剂诱导的心率增加。同型半胱氨酸增加细胞内钙和激活钙蛋白酶和钙蛋白酶相关的线粒体（mt）异常已被确定在HHcy。病理环境中的线粒体透化和解偶联由氧化还原应激和钙处理不当引起。最近，亲环素D，线粒体膜通透性转换孔的组成部分，在心肌缺血中的作用已被确定。NMDA-R激活和线粒体缺陷之间的增强作用导致HHcy期间心功能障碍的潜在机制仍有待阐明。本文综述了同型半胱氨酸通过激动NMDA-R而导致机械电功能下降和脑梗死的线粒体机制。线粒体MMP激活，蛋白酶应激和线粒体通透性转换在心脏传导过程中的假定作用进行了讨论。本文综述了同型半胱氨酸增加线粒体钙超载和氧化应激，增强线粒体基质金属蛋白酶的激活，导致线粒体通透性转换孔开放，导致机械-电功能障碍。
Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.