LARP1 acts as a key mediator in preventing angiotensin II-induced cardiac dysfunction and fibrosis.

Abstract

Background: Cardiac remodeling underlies many cardiovascular diseases and is characterized by cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis, leading to structural and functional deterioration of the heart. Angiotensin II (Ang II), a component of the renin-angiotensin system, drives pathological remodeling through hypertrophy and fibrosis. La-related protein 1 (LARP1), an RNA-binding protein involved in post-transcriptional regulation, has been implicated in cancer biology but its role in cardiovascular disease is largely unexplored. This study investigates the role of LARP1 in regulating Ang II-induced cardiac remodeling and its interaction with ATP2A2, a gene essential for calcium homeostasis.

Methods: Human cardiac tissues from hypertrophic cardiomyopathy patients and healthy controls were analyzed for LARP1 mRNA and protein expression. A murine model of Ang II-induced cardiac hypertrophy was established, and LARP1 expression was modulated using adeno-associated virus serotype 9 (AAV9)-LARP1 and gene-deficient mice. Primary cardiomyocytes and cardiac fibroblasts were treated with Ang II to study LARP1 function in vitro. RNA immunoprecipitation, RNA pull-down, and actinomycin D assays were performed to investigate the interaction between ATP2A2 mRNA and LARP1 protein. Cardiac function, hypertrophy, and fibrosis were evaluated through echocardiography, histological staining, and molecular analyses.

Results: LARP1 mRNA and protein expression were significantly downregulated in hypertrophic human and murine cardiac tissues and in Ang II-treated cardiomyocytes. LARP1 overexpression alleviated Ang II-induced cardiac remodeling, as evidenced by reduced cardiomyocyte size, fibrosis, and normalized expression of hypertrophy markers. In vivo, LARP1 overexpression improved cardiac function and reduced pathological changes in Ang II-treated mice. ATP2A2 was identified as a downstream target of LARP1, with LARP1 overexpression enhancing ATP2A2 mRNA stability and expression. Furthermore, ATP2A2 overexpression reversed hypertrophic and fibrotic changes in LARP1-deficient cardiomyocytes and mice, underscoring its critical role in mediating LARP1 protective effects.

Conclusions: LARP1 alleviates Ang II-induced cardiac remodeling in vivo and in vitro, potentially by stabilizing ATP2A2 mRNA and enhancing its expression, thereby reducing pathological remodeling. These findings establish LARP1 as a promising therapeutic target for preventing cardiac remodeling and highlight ATP2A2 as a key mediator of its protective effects. Future studies should explore the therapeutic potential of LARP1-based interventions in cardiovascular disease.