Met signaling in cardiomyocytes is required for normal cardiac function in adult mice
Met signaling in cardiomyocytes is required for normal cardiac function in adult mice
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DOI：
10.1016/j.bbadis.2013.08.008
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发表时间：
2013-12-01
影响因子：
6.2
通讯作者：
Porras, Almudena
中科院分区：
文献类型：
--
作者：
Arechederra, Maria;Carmona, Rita;Porras, Almudena
肝细胞生长因子(HGF)及其受体Met是不同发育过程的关键决定因素。尽管HGF在许多心脏病理中发挥心脏保护作用，但尚不清楚HGF/Met信号对成年心肌发育和/或生理功能是否必不可少。因此，我们使用Cre-α-MHC小鼠系(简称α-MHCMet-KO)，通过有条件地灭活心肌细胞中的Met受体，研究了心肌细胞中HGF/Met信号对胚胎和出生后心脏发育和功能的需求。尽管阿尔法-MHCMet-KO小鼠心脏发育正常，并且存活和生育，但在6个月大的时候，雄性小鼠出现了心肌细胞肥大，与间质纤维化有关。心肌损伤的标志物，如β-MIC和ANF也显著上调。在9个月大的时候，阿尔法-MHCMet-KO男性表现出收缩功能障碍。在机制上，我们提供了阿尔法-MHCMet-KO心脏抗氧化防御严重失衡的证据，包括过氧化氢酶和超氧化物歧化酶的表达和活性降低，从而导致活性氧积累。在雌性中也观察到了类似的异常，尽管运动速度较慢。我们还发现，Met信号下调导致转化生长因子-β产生增加，p38MAPK激活减少，这可能是导致α-MHCMet-KO小鼠表现出表型变化的原因之一。我们一贯地表明，HGF通过p38α上调心肌细胞中的抗氧化酶。我们的结果强调，心肌细胞中的HGF/Met信号通过氧化应激控制(C)2013 Elsevier B.V.作为心脏功能的内源性调节器，在成年小鼠中发挥生理性心脏保护作用。
Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-alpha-MHC mouse line (referred to as alpha-MHCMet-KO). Although alpha-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as beta-mic and ANF, was also observed. By the age of 9 months, alpha-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in alpha-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-beta production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in alpha-MHCMet-KO mice. Consistently, we show that HGF acts through p38 alpha to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control (C) 2013 Elsevier B.V. All rights reserved.