Characterization of the MEF2A target gene Myomaxin and its role in angiotensin II-induced cardiac pathophysiology.

摘要

The MEF2 family of transcription factors direct muscle-specific gene transcription and are critical in the development and function of the heart. The identification and functional characterization of genes regulated by MEF2 is of utmost importance in cardiovascular development and disease research. Recently, the striated muscle-specific MEF2A target gene Myomaxin was identified and cloned by our lab. The Myomaxin gene 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 the hypertrophic agonist, Angiotensin II (AngII). To uncover the in vivo requirement of Myomaxin we generated mice harboring a hypomorphic allele of the Myomaxin gene that resulted in a marked reduction in its expression in the heart and skeletal muscle. Adult Myomaxin hypomorphic mice are viable and fertile, yet display increased heart weight and ventricular myocyte cross-sectional area, two primary indicators of cardiac hypertrophy. This hypertrophic phenotype is accompanied by dysregulation of genes including beta myosin heavy chain (betamhc) a molecular marker of cardiomyopathy. Unlike other models of hypertrophic cardiomyopathy, Myomaxin hypomorphic mice do not display a significant accumulation of cardiac fibrosis or apoptosis. As Myomaxin is induced by AngII in vivo, we sought to determine its role in AngII-induced cardiomyopathy. Strikingly, Myomaxin hypomorphic mice chronically infused with AngII exhibit diminished pathological cardiac remodeling including an attenuated hypertrophic response, reduced fibrosis, and diminished apoptosis; suggesting that Myomaxin is required for the development of AngII-induced cardiac pathology. Thus in the absence of stress, Myomaxin is required for normal cardiac growth and homeostasis, yet reduced levels of the gene appear to be protective when the heart is subjected to AngII-induced stress. Finally, we demonstrate that AngII regulates Myomaxin transcription through an essential MEF2 binding site in the promoter and through the combined activity of MEF2A and STAT1, a transcriptional mediator of AngII signaling. These findings reveal a novel MEF2A-STAT1-Myomaxin pathway that functions downstream of AngII signaling to modulate its pathological effects in the heart.