Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction.
Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction.
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心肌细胞二甲基精氨酸二甲氨基水解酶-1 (DDAH1) 在减轻心室肥厚和功能障碍中发挥重要作用
DOI：
10.1007/s00395-017-0644-z
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发表时间：
2017-08-17
影响因子：
9.5
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Xu X;Zhang P;Kwak D;Fassett J;Yue W;Atzler D;Hu X;Liu X;Wang H;Lu Z;Guo H;Schwedhelm E;Böger RH;Chen P;Chen Y
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂，限制了一氧化氮的生物利用度。二甲基精氨酸二甲氨基水解酶-1 （DDAH1）在ADMA降解中起关键作用，并在NO信号传导中发挥重要作用。在心脏中，在内皮细胞和心肌细胞的肌膜中观察到DDAH1。虽然NO信号对于心脏适应应激很重要，但DDAH1对心肌细胞稳态的影响尚不清楚。在这里，我们使用MerCreMer-LoxP模型特异性破坏成年小鼠心肌细胞DDAH1的表达，以确定心肌细胞DDAH1在基础条件下和横断主动脉收缩（TAC）引起的肥厚应激期间的生理影响。在对照条件下，心肌细胞特异性DDAH1基因敲除（cdddah KO）对成年或衰老小鼠血浆ADMA和左心室（LV）肥大或功能没有可检测到的影响。在TAC的作用下，WT小鼠的DDAH1水平升高了2.5倍，左室和血浆ADMA含量没有变化，左室中度肥大和左室功能障碍。相比之下，暴露于TAC的cDDAH1 KO小鼠左室DDAH1表达未增加，左室组织ADMA水平略有升高，血浆ADMA未增加，但左室肥大、纤维化、硝基酪氨酸生成和左室功能障碍明显加重。这些发现表明，在基础条件下，心肌细胞DDAH1活性对心功能是必不可少的，但在应激条件下，它在减轻心脏肥厚和心室重构中发挥重要作用，可能是通过局部限制亚细胞ADMA和NO信号的调节。
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases that limits nitric oxide bioavailability. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) exerts a critical role for ADMA degradation and plays an important role in NO signaling. In the heart, DDAH1 is observed in endothelial cells and in the sarcolemma of cardiomyocytes. While NO signaling is important for cardiac adaptation to stress, DDAH1 impact on cardiomyocyte homeostasis is not clear. Here we used the MerCreMer-LoxP model to specifically disrupt cardiomyocyte DDAH1 expression in adult mice to determine the physiological impact of cardiomyocyte DDAH1 under basal conditions and during hypertrophic stress imposed by transverse aortic constriction (TAC). Under control conditions, Cardiomyocyte specific DDAH1 knockout (cDDAH KO) had no detectable effect on plasma ADMA and left ventricular (LV) hypertrophy or function in adult or aging mice. In response to TAC, DDAH1 levels were elevated 2.5 fold in WT mice, which exhibited no change in LV or plasma ADMA content and moderate LV hypertrophy and LV dysfunction. In contrast, cDDAH1 KO mice exposed to TAC showed no increase in LV DDAH1 expression, slightly increased LV tissue ADMA levels, no increase in plasma ADMA, but significantly exacerbated LV hypertrophy, fibrosis, nitrotyrosine production, and LV dysfunction. These findings indicate cardiomyocyte DDAH1 activity is dispensable for cardiac function under basal conditions, but plays an important role in attenuating cardiac hypertrophy and ventricular remodeling under stress conditions, possibly through locally confined regulation of subcellular ADMA and NO signaling.
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影响因子：
37.8
作者：
Chen, YJ;Traverse, JH;Bache, RJ
通讯作者：
Bache, RJ
DOI：
10.1152/ajpheart.01236.2006
发表时间：
2007-07-01
影响因子：
4.8
作者：
Buys, Emmanuel S.;Raher, Michael J.;Scherrer-Crosbie, Marielle
通讯作者：
Scherrer-Crosbie, Marielle
DOI：
10.1161/atvbaha.110.222638
发表时间：
2011-07
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Hu X;Atzler D;Xu X;Zhang P;Guo H;Lu Z;Fassett J;Schwedhelm E;Böger RH;Bache RJ;Chen Y
通讯作者：
Chen Y
影响因子：
5.5
作者：
Jagnandan, D;Sessa, WC;Fulton, D
通讯作者：
Fulton, D
影响因子：
3.7
作者：
Meng, Nana;Zhang, Ping;Qu, Yi
通讯作者：
Qu, Yi