Angiotensin II-induced cardiac dysfunction and fibrosis is prevented by cardiomyocyte-specific overexpression of Larp6

Abstract

Introduction: La ribonucleoprotein 6, Translational Regulator (Larp6) is a multifunctional mRNA binding protein most well described for its pro-fibrotic action to increase type I collagen mRNA half-life, translation, and deposition. In the heart, the actions of Larp6 are not described. Interestingly, Larp6 is expressed in cardiomyocytes which are not primarily involved in cardiac fibrosis. To investigate the role of cardiomyocyte Larp6 in cardiac function and remodeling, we generated a cardiomyocyte-specific Larp6 overexpressing (OE) transgenic mouse model and determined its role at (i) baseline and (ii) following hypertensive challenge with angiotensin II (Ang II). We hypothesized that cardiomyocyte-specific Larp6 OE exacerbates Ang II-induced cardiac remodeling and dysfunction. Methods: Cross-sectional studies were performed from 2-8 months of age in male and female Larp6 OE and wildtype (WT) littermates. Baseline cardiac function was assessed by 7-T MRI and echocardiography. In a separate set of mice (10 mo of age), hypertension was induced via Ang II infusion by osmotic minipump (1000 ng/kg/min) or vehicle. Blood pressure (BP) was assessed 14-17 days post-infusion via tail-cuff plethysmography, cardiac function by echocardiography after 21 days, and the heart prepared for histochemistry. Differences in endpoints were determined by two-way ANOVA with Tukey post hoc and a significant p-value cutoff of 0.05. Results: Baseline studies revealed Larp6 OE had no significant effect on cardiac function (7-T MRI), BP, or gross morphology in either sex across timepoints. At 10 months of age, histochemistry revealed increased cardiomyocyte Larp6 protein expression and mild, but significant, interstitial fibrosis in unstressed Larp6 OE mice. In 10-month-old mice, Ang II infusion similarly increased BP and induced cardiac hypertrophy in both male and female Larp6 OE and WT mice. Further, Ang II induced systolic dysfunction and cardiac fibrosis in WT mice. Unexpectedly, Larp6 OE prevented Ang II-mediated interstitial fibrotic remodeling and decreases in ejection fraction, fractional shortening, and cardiac output independent of sex. Of note, Larp6 OE did not protect against Ang II-induced perivascular fibrosis, suggesting the anti-fibrotic effect was localized around the cardiomyocytes. Conclusion: Taken together, these data support a pro-fibrotic action of cardiomyocyte Larp6 in unstressed mice. Despite this impact at baseline, cardiomyocyte-specific Larp6 OE is suffcient to prevent Ang II-induced cardiac fibrosis and dysfunction, independent of BP and sex. This unexpected result, contrary to our hypothesis, suggests that targeting cardiomyocyte Larp6 signaling may represent a new therapeutic avenue to treat hypertensive heart disease. R01 HL136386, NIDDK DK130243, SRCS (IK6BX004016), BX005845, and R21 AA029747. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.