Modulation of Angiotensin II–Mediated Cardiac Remodeling by the MEF2A Target Gene Xirp2

Abstract

4 suggesting that CMYA3 is directly regulated by Ang II signaling. This gene, since named Xirp2 (also known as mXin␤ and myomaxin), is a direct target of the MEF2A transcription factor and is markedly downregulated in hearts lacking MEF2A. 5,6 Xirp2 belongs to the ancient, muscle-specific, actin-binding Xin gene family whose expression can be traced to ancestral vertebrates with a 2-chambered heart. 7-9 Xirp2 is expressed in cardiac and skeletal muscle where it interacts with filamentous actin and ␣-actinin through the novel actin-binding motif, the Xin repeat. 5,8 In striated muscle, Xirp2 localizes to the peripheral Z-disc region, or costamere, 5 and the intercalated disk. 10,11 The subcellular localization of Xirp2 is significant in that the costamere and intercalated disk harbor mechanical stress sensors that are critical for normal muscle function. [12][13][14] Antisense knockdown of Xin in developing chick embryos, the sole Xin family member in this species, results in a severe disruption of cardiac looping morphogenesis. 9 In mice, a lossof-function mutation of mXin␣, the mammalian ortholog of Xin, results in cardiomyopathy and conduction defects. 11 In the present study we sought to determine the role of Xirp2 in cardiac development and/or function. Mice harboring a hypomorphic Xirp2 allele are viable but display cardiac hypertrophy. As Xirp2 is regulated by Ang II, we also examined cardiac pathology in hypomorphic mice with long-term administration of this hormone. In contrast to wild type mice exposed to a chronic Ang II infusion, hypomorphic mice displayed diminished cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, we demonstrate that regulation of Xirp2 gene expression in response to Ang II signaling is mediated by MEF2A. Our results suggest that Original

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

“…Cell Culture-C2C12 and COS cells were cultured as described previously (14). Specificity of the Mef2b and Mef2d shRNAs was tested by co-transfection of COS cells with MEF2-FLAG and pENTR shRNA constructs.…”

Cardioprotective properties of bradykinin: role of the B2 receptor

“…62 More recently, we have found that Ang II in vivo and in vitro stimulates gene overexpression of various vasoactive factors, including the B 1 R and B 2 R genes 53 as well as a novel gene, the cardiomyopathy-associated 3, also known as myomaxin and recently renamed Xirp2. [63][64][65] Although this gene's product remains unknown, its contribution to ischemic cardiomyopathy is crucial, as shown by studies in genetically engineered mice. 65 Interestingly, concurrent inhibition of the AT 1 receptor of Ang II with losartan can abolish the BK receptor upregulation.…”

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

“…The control group received same amount of sterile saline. The angiotensin II (AngII)–induced cardiac injury model was performed, as previously reported 26, 27, 28, 29, 30, 31. Human AngII protein (A9525; Sigma‐Aldrich) was dissolved with sterile saline.…”