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Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca\n<jats:sup>2+<\/jats:sup> overload. In this study, we investigated the effects of ranolazine on pressure overload\u2010induced cardiac hypertrophy and heart failure in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca<jats:sup>2+<\/jats:sup> imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca\n<jats:sup>2+<\/jats:sup> release and increased SR Ca\n<jats:sup>2+<\/jats:sup> leak. Ranolazine restored aberrant SR Ca\n<jats:sup>2+<\/jats:sup> handling induced by pressure overload. Ranolazine also suppressed Na\n<jats:sup>+<\/jats:sup> overload induced in the failing heart, and restored Na\n<jats:sup>+<\/jats:sup>\u2010induced Ca\n<jats:sup>2+<\/jats:sup> overload in an sodium\u2010calcium exchanger (NCX)\u2010dependent manner. Ranolazine suppressed the Ca\n<jats:sup>2+<\/jats:sup>\u2010dependent calmodulin (CaM)\/CaMKII\/myocyte enhancer factor\u20102\u00a0(MEF2) and CaM\/CaMKII\/calcineurin\/nuclear factor of activated T\u2010cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER\u2010initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER\u2010initiated cardiomyocyte apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload\u2010induced cardiac hypertrophy and systolic and diastolic function by restoring Na<jats:sup>+<\/jats:sup> and Ca\n<jats:sup>2+<\/jats:sup> handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.27791","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T09:43:27Z","timestamp":1543484607000},"page":"11587-11601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Ranolazine prevents pressure overload\u2010induced cardiac hypertrophy and heart failure by restoring aberrant Na<sup>+<\/sup> and Ca<sup>2+<\/sup> handling"],"prefix":"10.1002","volume":"234","author":[{"given":"Jiali","family":"Nie","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanlu","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"He","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianqing","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujin","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4316-2459","authenticated-orcid":false,"given":"Zheng","family":"Wen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China"},{"name":"Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao Wu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital, Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherina M.","family":"Alsina","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology &amp; 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