Abstract
Background: A deregulated aldosterone (Aldo)-mineralocorticoid receptor (MR) pathway is linked to cardiovascular disease (CVD), including hypertension and heart failure. Despite the association of elevated plasma Aldo levels with cardiac stress, inflammation, myocardial fibrosis, and cardiac remodeling, the underlying mechanisms remain elusive. Methods: To study the impact of Aldo-MR pathway overactivation on cardiac health, a novel mouse model with AAV9-mediated MR overexpression and Aldo administration via subcutaneous osmotic pumps was generated. Echocardiographic analyses, transcriptome sequencing, and loss-of-function experiments of an identified lead candidate gene were performed. Additionally, cardiac tissue samples from human patients with end-stage heart failure were analyzed in the study. Results: Mice with an overactivated Aldo-MR pathway exhibited increased neutrophil gelatinase-associated lipocalin (NGAL) expression, cardiac dysfunction, hypertrophy, and fibrosis. Transcriptomics identified prostaglandin D2 synthase (Ptgds) as a novel downstream effector of the cardiac Aldo-MR pathway. SiRNA-mediated inhibition of Ptgds in primary cardiomyocytes reduced NGAL levels and the hypertrophic impact of Aldo, suggesting a role in mediating Aldo-induced cardiac pathologies. Elevated expression of PTGDS was observed in hiPSC-CMs treated with the pro-hypertrophic cytokine leukemia inhibitory factor (LIF) and in end-stage heart failure patients, ascertaining its importance in cardiac disease settings. Conclusions: PTGDS is a newly identified mediator of Aldo-MR-induced cardiac remodeling and may represent a potential therapeutic target for CVD.
Keywords:
Aldo–MR pathway; adeno-associated virus; cardiac hypertrophy; cardiovascular disease; remodeling.