Ranolazine Prevents Pressure Overload-induced Cardiac Hypertrophy and Heart Failure by Restoring Aberrant Na and Ca Handling

Overview

Journal J Cell Physiol

Specialties Cell Biology
Physiology

Date 2018 Nov 30

PMID 30488495

Citations 25

Authors

Jiali Nie

Quanlu Duan

Mengying He

Xianqing Li

Bei Wang

Chi Zhou

Lujin Wu

Zheng Wen

Chen Chen

Dao Wu Wang

Katherina M Alsina

Xander H T Wehrens

Dao Wen Wang

Li Ni

Affiliations

Soon will be listed here.

Abstract

Background: Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 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 imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca release and increased SR Ca leak. Ranolazine restored aberrant SR Ca handling induced by pressure overload. Ranolazine also suppressed Na overload induced in the failing heart, and restored Na -induced Ca overload in an sodium-calcium exchanger (NCX)-dependent manner. Ranolazine suppressed the Ca -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 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.

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