Cardiomyocyte-specific LARP6 overexpression prevents angiotensin II-induced myocardial dysfunction and interstitial fibrosis.

La ribonucleoprotein 6, translational regulator (LARP6), a multifunctional mRNA-binding protein with well-described profibrotic effects, increases type I collagen mRNA half-life, translation, and deposition in noncardiac tissues. In the heart, LARP6 is expressed in cardiomyocytes, not primarily involved in fibrosis, where its role is unknown. To investigate the role of cardiomyocyte-derived LARP6 on cardiac function and remodeling, we generated a cardiomyocyte-specific LARP6 overexpressing transgenic mouse model (LARP6-Tg). Baseline longitudinal studies up to 10 mo of age revealed that constitutive overexpression of LARP6 had no significant effect on cardiac function or morphology despite inducing mild interstitial fibrosis versus wild-type (WT) littermates. Subsequently, we hypothesized that cardiomyocyte-specific LARP6-Tg mice would exhibit exacerbated cardiac remodeling and dysfunction in response to hypertensive stress via angiotensin II (Ang II) infusion. Ang II (1000 ng/kg/min for 21 days) induced hypertension and cardiac hypertrophy in WT and LARP6-Tg mice of both sexes. Unexpectedly, Ang II-induced cardiac dysfunction was prevented in LARP6-Tg mice. Cardiac gene expression profiling predicted increased fibrosis and cardiomyocyte death in Ang II-treated WT mice and inhibition of cardiomyocyte death in Ang II-treated LARP6-Tg mice versus saline-treated controls. Surprisingly, Ang II-induced interstitial fibrosis was reduced in LARP6-Tg mice and associated with attenuation of cardiomyocyte cell death and reduced fibroblast activation. These data support a mild profibrotic action of cardiomyocyte-specific LARP6 overexpression in unstressed mice and, paradoxically, that LARP6 overexpression is sufficient to prevent Ang II-induced cardiac interstitial fibrosis and dysfunction. Sustained induction of LARP6 has therapeutic potential in hypertensive heart disease.