Atrial TRPM2 Channel-Mediated Ca²⁺ Influx Regulates ANP Secretion and Protects Against ISO-Induced Cardiac Hypertrophy and Fibrosis

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca2+-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. We compared how wild-type (WT) and TRPM2 knockout (TRPM2−/−) mice respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca2+ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in the atria of WT mice, and measured ADP-ribose (ADPr)–evoked currents as well as hydrogen peroxide (H2O2)–induced Ca2+ influx characteristic for TRPM2 of WT atrial myocytes; these were absent in TRPM2−/− cells. Under the ISO-induced hypertrophic model, TRPM2−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling.