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

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.

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.

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.

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.