Department of Biology, Boston University, 24 Cummington St, Boston, MA 02215, USA.
Circ Res. 2010 Mar 19;106(5):952-60. doi: 10.1161/CIRCRESAHA.109.209007. Epub 2010 Jan 21.
The vasoactive peptide angiotensin II (Ang II) is a potent cardiotoxic hormone whose actions have been well studied, yet questions remain pertaining to the downstream factors that mediate its effects in cardiomyocytes.
The in vivo role of the myocyte enhancer factor (MEF)2A target gene Xirp2 in Ang II-mediated cardiac remodeling was investigated.
Here we demonstrate that the MEF2A target gene Xirp2 (also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart. Xirp2 belongs to the evolutionarily conserved, muscle-specific, actin-binding Xin gene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized the Xirp2 promoter and demonstrate that Ang II activates Xirp2 expression by stimulating MEF2A transcriptional activity. To further characterize the role of Xirp2 downstream of Ang II signaling we generated mice harboring a hypomorphic allele of the Xirp2 gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adult Xirp2 hypomorphic mice displayed cardiac hypertrophy and increased beta myosin heavy chain expression. Strikingly, Xirp2 hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis.
These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart.
血管活性肽血管紧张素 II（Ang II）是一种强效的心脏毒性激素，其作用已得到充分研究，但对于介导其在心肌细胞中作用的下游因子仍存在疑问。
研究肌细胞增强因子 2A（MEF2A）靶基因 Xirp2 在血管紧张素 II 介导的心脏重构中的体内作用。
本研究证明，MEF2A 靶基因 Xirp2（也称为心肌病相关基因 3 [CMYA3]）是心脏中血管紧张素 II 信号通路的重要效应因子。Xirp2 属于进化保守的、肌肉特异性的、肌动蛋白结合的 Xin 基因家族，对全身给予血管紧张素 II 有明显的诱导作用。首先，我们对 Xirp2 启动子进行了特征描述，并证明血管紧张素 II 通过刺激 MEF2A 转录活性激活 Xirp2 表达。为了进一步研究 Xirp2 在血管紧张素 II 信号下游的作用，我们生成了携带 Xirp2 基因低功能等位基因的小鼠，导致其在心脏中的表达明显减少。在没有血管紧张素 II 的情况下，成年 Xirp2 低功能小鼠表现出心脏肥大和β肌球蛋白重链表达增加。引人注目的是，慢性给予血管紧张素 II 的 Xirp2 低功能小鼠表现出改变的病理性心脏重构，包括肥大反应减弱，以及纤维化和细胞凋亡减少。
这些发现揭示了一种新的 MEF2A-Xirp2 通路，该通路在血管紧张素 II 信号下游发挥作用，调节其在心脏中的病理性作用。
