Rationale: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.Objective:The in vivo role of the myocyte enhancer factor (MEF)2A target geneXirp2in Ang II–mediated cardiac remodeling was investigated.Methods and Results:Here we demonstrate that the MEF2A target geneXirp2(also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart.Xirp2belongs to the evolutionarily conserved, muscle-specific, actin-bindingXingene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized theXirp2promoter and demonstrate that Ang II activatesXirp2expression 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 theXirp2gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adultXirp2hypomorphic mice displayed cardiac hypertrophy and increased β myosin heavy chain expression. Strikingly,Xirp2hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis.Conclusions:These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart.