J Hypertens. 2026 Feb 20. doi: 10.1097/HJH.0000000000004273. Online ahead of print.
ABSTRACT
INTRODUCTION: Hypertension poses a significant threat to human health through its induction of cardiac damage. The calcium-sensing receptor (CaSR) has been implicated in cardiovascular diseases; however, its specific role in cardiomyocyte injury in spontaneously hypertensive rats (SHRs) remains unclear. This study therefore investigated the effects of Calhex231, a CaSR antagonist, on cardiac damage in SHRs.
METHODS: Cardiac function and structure were evaluated by echocardiography, histological staining and transmission electron microscopy. To explore the underlying mechanisms, CaSR expression along with markers of mitophagy, autophagy and apoptosis were assessed in rat hearts tissues via Western blotting. Furthermore, mitochondrial membrane potential and intracellular calcium levels were measured in angiotensin II (Ang II)-treated cardiomyocytes at the cellular level.
RESULTS: Relative to WKY rats, SHRs showed elevated blood pressure, cardiac injury (hypertrophy, fibrosis, apoptosis), and upregulated CaSR, mitophagy and autophagy. Calhex231 reversed these in-vivo pathologies and, in vitro, protected cardiomyocytes against Ang II-induced apoptosis. This protection was achieved by inhibiting mitophagy/autophagy, lowering [Ca2+]i, and preserving mitochondrial membrane potential. The pivotal role of CaSR was underscored by the fact that its knockdown reproduced the protective effects against Ang II.
CONCLUSION: These findings suggests that Calhex231 protects against cardiomyocyte apoptosis by inhibiting both the PINK1/Parkin-mediated mitophagy pathway and general autophagy. Therefore, targeting the CaSR represents a promising therapeutic strategy to prevent cardiac damage induced by hypertension.
PMID:41818401 | DOI:10.1097/HJH.0000000000004273