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Ranolazine prevents pressure overload‐induced cardiac hypertrophy and heart failure by restoring aberrant Na + and Ca 2+ handling
Author(s) -
Nie Jiali,
Duan Quanlu,
He Mengying,
Li Xianqing,
Wang Bei,
Zhou Chi,
Wu Lujin,
Wen Zheng,
Chen Chen,
Wang Dao Wu,
Alsina Katherina M.,
Wehrens Xander H.T.,
Wang Dao Wen,
Ni Li
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27791
Subject(s) - pressure overload , ranolazine , muscle hypertrophy , medicine , heart failure , endoplasmic reticulum , myocyte , endocrinology , nfat , mef2 , calcineurin , cardiac function curve , cardiology , chemistry , biochemistry , cardiac hypertrophy , enhancer , transplantation , transcription factor , gene
Background Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca 2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload‐induced cardiac hypertrophy and heart failure in mice. Methods and Results 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 2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na + ‐induced Ca 2+ overload in an sodium‐calcium exchanger (NCX)‐dependent manner. Ranolazine suppressed the Ca 2+ ‐dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor‐2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T‐cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER‐initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER‐initiated cardiomyocyte apoptosis. Conclusions Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload‐induced cardiac hypertrophy and systolic and diastolic function by restoring Na + and Ca 2+ 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.