{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:55:11Z","timestamp":1791910511737,"version":"4.3.4"},"reference-count":77,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Ischemic heart disease is one of the leading causes of death worldwide. Timely reperfusion is necessary for myocardium salvage but triggers paradoxical cardiomyocyte death and contributes to up to 50% of the final infarct size, known as lethal ischemia\/reperfusion (I\/R) injury. TRPM7 (transient receptor potential melastatin 7) is a divalent cation\u2013permeable, nonselective channel kinase that can sense oxidative stress and release Zn\n                      <jats:sup>2+<\/jats:sup>\n                      from unique intracellular TRPM7 vesicles. However, the pathophysiological role of intracellular TRPM7 remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      TRPM7 expression was determined in hearts from patients with ischemic heart failure and I\/R-injured mice. Global (\n                      <jats:italic toggle=\"yes\">\n                        gTrpm7\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      ), cardiomyocyte-specific (\n                      <jats:italic toggle=\"yes\">cmTrpm7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      ), and fibroblast-specific (\n                      <jats:italic toggle=\"yes\">fibTrpm7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      )\n                      <jats:italic toggle=\"yes\">Trpm7<\/jats:italic>\n                      knockout mice were used to determine the role of TRPM7 in I\/R injury. Mechanistic investigations were conducted in neonatal and adult mouse cardiomyocytes and human induced pluripotent stem cell\u2013derived cardiomyocytes (hiPSC-CMs) with patch-clamp, Zn\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      imaging, and molecular biology techniques. An inducible TRPM7 channel-dead (TRPM7-E1047K) knock-in mouse model was generated to elucidate the functional domains of TRPM7 for therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found that TRPM7 was significantly upregulated in myocardium from both patients with ischemic heart failure and I\/R-injured mice. Global TRPM7 deficiency markedly reduced infarct size and improved cardiac function after I\/R injury. Using\n                      <jats:italic toggle=\"yes\">cmTrpm7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic toggle=\"yes\">fibTrpm7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, we demonstrated that TRPM7 deficiency in myocytes, rather than in fibroblasts, confers protection against I\/R injury by inhibiting pyroptosis as evaluated. Furthermore, using mouse cardiomyocytes and hiPSC-CMs, we revealed that Zn\n                      <jats:sup>2+<\/jats:sup>\n                      release from intracellular TRPM7 vesicles during I\/R injury triggers cardiomyocyte death by activating gasdermin-D to release its N-terminal and form the membrane pore. The critical role of intracellular TRPM7 was further supported by the inability of membrane TRPM7 inhibition to protect mice against I\/R injury. To elucidate whether the channel or kinase activity of TRPM7 mediates pyroptosis in I\/R injury, we generated an inducible channel-dead TRPM7-E1047K knock-in mouse model. By comparing with kinase-inactive TRPM7 knock-in mice, we uncovered that the channel but not the kinase function of TRPM7 mediates I\/R injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      TRPM7-mediated intracellular Zn\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      release contributes to myocardial I\/R injury by triggering apoptotic and pyroptotic cardiomyocyte death. Given that TRPM7 is highly upregulated in patients with ischemic heart failure, our findings suggest that targeting TRPM7 may represent a novel therapeutic strategy for ischemic heart disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074791","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:00:15Z","timestamp":1770372015000},"page":"1210-1229","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["TRPM7 Deficiency Protects Against Myocardial Ischemia-Reperfusion Injury by Regulating Intracellular Zn\n                    <sup>2+<\/sup>\n                    Homeostasis"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1205-1976","authenticated-orcid":true,"given":"Xin","family":"Li","sequence":"first","affiliation":[{"name":"Pat and Jim Calhoun Cardiology Center (Xin Li, Xiaohan Li, C.X.L., 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