Open AccessNewly Identified NO ‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function
Author(s) -
Crassous PierreAntoine,
Shu Ping,
Huang Can,
Gordan Richard,
Brouckaert Peter,
Lampe Paul D.,
Xie LaiHua,
Beuve Annie
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.117.006397
Subject(s) - connexin , soluble guanylyl cyclase , medicine , gap junction , intercalated disc , phosphorylation , knockout mouse , angiotensin ii , ventricular remodeling , signal transduction , endocrinology , microbiology and biotechnology , nitric oxide , heart failure , biology , intracellular , guanylate cyclase , receptor
Background Guanylyl cyclase, a heme‐containing α1β1 heterodimer ( GC 1), produces cGMP in response to Nitric oxide ( NO ) stimulation. The NO ‐ GC1 ‐ cGMP pathway negatively regulates cardiomyocyte contractility and protects against cardiac hypertrophy–related remodeling. We recently reported that the β1 subunit of GC 1 is detected at the intercalated disc with connexin 43 (Cx43). Cx43 forms gap junctions ( GJs ) at the intercalated disc that are responsible for electrical propagation. We sought to determine whether there is a functional association between GC 1 and Cx43 and its role in cardiac homeostasis. Methods and Results GC 1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC 1 and Cx43 are associated. Mice lacking the α subunit of GC 1 ( GC α1 knockout mice) displayed a significant decrease in GJ function (dye‐spread assay) and Cx43 membrane lateralization. In a cardiac‐hypertrophic model, angiotensin II treatment disrupted the GC1‐Cx43 association and induced significant Cx43 membrane lateralization, which was exacerbated in GC α1 knockout mice. Cx43 lateralization correlated with decreased Cx43‐containing GJs at the intercalated disc, predictors of electrical dysfunction. Accordingly, an ECG revealed that angiotensin II –treated GC α1 knockout mice had impaired ventricular electrical propagation. The phosphorylation level of Cx43 at serine 365, a protein‐kinase A upregulated site involved in trafficking/assembly of GJs , was decreased in these models. Conclusions GC 1 modulates ventricular Cx43 location, hence GJ function, and partially protects from electrical dysfunction in an angiotensin II hypertrophy model. Disruption of the NO ‐ cGMP pathway is associated with cardiac electrical disturbance and abnormal Cx43 phosphorylation. This previously unknown NO /Cx43 signaling could be a protective mechanism against stress‐induced arrhythmia.