Open AccessSodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes
Author(s) -
Rivaud Mathilde R.,
AgulloPascual Esperanza,
Lin Xianming,
LeoMacias Alejandra,
Zhang Mingliang,
Rothenberg Eli,
Bezzina Connie R.,
Delmar Mario,
Remme Carol Ann
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007622
Subject(s) - sodium channel , microtubule , medicine , heart failure , microbiology and biotechnology , intercalated disc , nav1.5 , gap junction , sodium , intracellular , biology , chemistry , organic chemistry
Background Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure. Methods and Results Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (I Na ) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, I Na in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased I Na and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average Na V 1.5 cluster size at the LM of TAC cells, in line with reduced I Na . Conclusions Heart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in Na V 1.5 clustering and I Na within distinct subcellular microdomains of failing cardiomyocytes.