The Gαi/o GPCR LPAR2 Acts as a Non-Classical Factor for Aldosterone Induced Injury in a Cardiomyocyte Model

The hormone aldosterone, crucial for maintaining sodium, potassium, and fluid balance in the body, can lead to cardiac hypertrophy, inflammation, fibrosis, and heart failure when chronically elevated, as seen in conditions like primary aldosteronism, chronic heart and kidney diseases, and aging. Traditionally, this detrimental impact of aldosterone was considered to be mediated solely by the mineralocorticoid receptor (MR).

However, recent studies suggest that non-classical G protein-coupled receptor (GPCR) signaling, specifically through the lysophosphatidic acid receptor 2 (LPAR2), also plays a role in aldosterone's effects on cardiomyocytes.

To explore this, the research utilized AC16 human cardiomyocyte cells and reporter gene assays, which revealed that aldosterone activates a Gi/o-dependent GPCR pathway. Pharmacological inhibition of LPAR2 internalization confirmed its specific response to aldosterone. Functional studies further demonstrated that aldosterone-induced cardiomyocyte injury requires the simultaneous involvement of both MR and LPAR2.

Specifically, using specific antagonists for both receptors was found to significantly reduce the ability of aldosterone to increase collagen expression and activate cell death markers.

This groundbreaking research uncovers a previously unknown non-classical mechanism through which aldosterone exerts its deleterious effects on the heart. By identifying LPAR2 as a promising therapeutic target, this study opens up new avenues for developing treatments aimed at mitigating aldosterone-driven cardiovascular diseases.