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

Sep 30, 2026

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Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable, redox-activated cardiac ion channel with known cardioprotective roles in ischemia–reperfusion, but its function in atrial endocrine output under stress remains unresolved. Using male C57BL/6J wild-type and TRPM2 knockout mice exposed to β-adrenergic isoproterenol, TRPM2 deficiency amplified ISO-induced hypertrophy, fibrosis, and systolic dysfunction. TRPM2−/− animals showed blunted Nppa/ANP induction and reduced circulating ANP despite ISO stimulation, while exogenous ANP restored endocrine and functional phenotypes, indicating a TRPM2-dependent, ANP-mediated cardioprotective pathway.

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CategoryResearch & Report

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Article Atrial TRPM2 Channel-Mediated Ca2+ Influx Regulates ANP Secretion and Protects Against Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis Tomohiro Numata 1, *, Hideaki Tagashira 1, Kaori Sato-Numata 1, Meredith C Hermosura 2, Fumiha Abe 1, Ayako Sakai 1, Shinichiro Yamamoto 3 and Hiroyuki Watanabe 4 Academic Editors: David J. Grieve and Sobuj Mia Received: 14 November 2025 Revised: 17 December 2025 Accepted: 19 December 2025 Published: 22 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Integrative Physiology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan; [htagashira@med.akita-u.ac.jp](htagashira@med.akita-u.ac.jp) (H.T.); [satokao@med.akita-u.ac.jp](satokao@med.akita-u.ac.jp) (K.S.-N.); [f_abe@hos.akita-u.ac.jp](f_abe@hos.akita-u.ac.jp) (F.A.); [a.sakai@med.akita-u.ac.jp](a.sakai@med.akita-u.ac.jp) (A.S.) 2 John A. Burns School of Medicine, Honolulu, HI 96813, USA; [hermosur@hawaii.edu](hermosur@hawaii.edu) 3 Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo 164-8530, Japan; [s.yamamoto@thu.ac.jp](s.yamamoto@thu.ac.jp) [4](4 Department of Cardiovascular Medicine)[ Department of Cardiovascular Medicine](4 Department of Cardiovascular Medicine), [Akita University Graduate School of Medicine](Akita University Graduate School of Medicine), [Akita 010-8543](Akita 010-8543), Japan; [hirow@doc.med.akita-u.ac.jp](hirow@doc.med.akita-u.ac.jp) * [Correspondence: numata@med.akita-u.ac.jp](Correspondence: numata@med.akita-u.ac.jp); Tel.: +81-18-884-6272 Highlights What are the main findings? • TRPM2 is functionally enriched in atrial cardiomyocytes and drives stress-evoked Ca2+ influx that triggers ANP secretion. • TRPM2 deficiency exacerbates ISO-induced hypertrophy, fibrosis, and systolic dysfunction, with blunted Nppa/ANP induction; exogenous ANP rescues these phenotypes. What are the implications of the main findings? • TRPM2 functions as an upstream Ca2+-dependent regulator of the cardiac natriuretic peptide system, extending its known roles beyond oxidative-stress sensing. • Therapeutic augmentation of the ANP axis (e.g., ANP administration, neprilysin inhibition) or targeting TRPM2 may mitigate pathological cardiac remodeling in hypertension and heart failure. Abstract Transient receptor potential melastatin 2 (TRPM2) channel is a Ca2+-permeable, redoxactivated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2−/−) mice (8–12 weeks old) 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 WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H 2O2 )-induced Ca2+ influx characteristic of TRPM2; 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.

FAQs

What main role does TRPM2 play in the atrial response to stress in this study?

TRPM2 supports stress-evoked Ca2+ influx in atrial cardiomyocytes that triggers ANP secretion during β-adrenergic stimulation.

How does TRPM2 deficiency affect isoproterenol (ISO)-induced cardiac remodeling?

TRPM2 knockout mice develop more severe ISO-induced hypertrophy and fibrosis and exhibit worsened systolic dysfunction compared with wild-type controls.

Why is exogenous ANP important to the conclusions?

Administering exogenous ANP attenuates the ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2−/− mice, supporting that TRPM2’s cardioprotection requires an ANP-mediated endocrine response.

Sep 30, 2026

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