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Newly identified NO-sensor guanylyl cyclase/connexin 43 association is involved in cardiac electrical function

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Abstract
Background: Guanylyl cyclase, a heme-containing alpha 1 beta 1 heterodimer (GC1), 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 beta 1 subunit of GC1 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 GC1 and Cx43 and its role in cardiac homeostasis. Methods and Results: GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the alpha subunit of GC1 (GC alpha 1 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 alpha 1 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 GCa1 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: GC1 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.
Keywords
ACTIVATED INWARD CURRENT, SUDDEN ARRHYTHMIC DEATH, NITRIC-OXIDE, SYNTHASE, PROTEIN-KINASE I, HEART-RATE, MEMBRANE ASSOCIATION, SODIUM-CHANNELS, KNOCKOUT MICE, GAP-JUNCTIONS, UP-REGULATION, arrhythmia, cardiac function, cardiovascular disease, cGMP, connexin 43, guanylyl cyclase, Nitric oxide

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Citation

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Chicago
Crassous, Pierre-Antoine, Ping Shu, Can Huang, Richard Gordan, Peter Brouckaert, Paul D Lampe, Lai-Hua Xie, and Annie Beuve. 2017. “Newly Identified NO-sensor Guanylyl Cyclase/connexin 43 Association Is Involved in Cardiac Electrical Function.” Journal of the American Heart Association 6 (12).
APA
Crassous, P.-A., Shu, P., Huang, C., Gordan, R., Brouckaert, P., Lampe, P. D., Xie, L.-H., et al. (2017). Newly identified NO-sensor guanylyl cyclase/connexin 43 association is involved in cardiac electrical function. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 6(12).
Vancouver
1.
Crassous P-A, Shu P, Huang C, Gordan R, Brouckaert P, Lampe PD, et al. Newly identified NO-sensor guanylyl cyclase/connexin 43 association is involved in cardiac electrical function. JOURNAL OF THE AMERICAN HEART ASSOCIATION. 2017;6(12).
MLA
Crassous, Pierre-Antoine, Ping Shu, Can Huang, et al. “Newly Identified NO-sensor Guanylyl Cyclase/connexin 43 Association Is Involved in Cardiac Electrical Function.” JOURNAL OF THE AMERICAN HEART ASSOCIATION 6.12 (2017): n. pag. Print.
@article{8547074,
  abstract     = {Background: Guanylyl cyclase, a heme-containing alpha 1 beta 1 heterodimer (GC1), 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 beta 1 subunit of GC1 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 GC1 and Cx43 and its role in cardiac homeostasis. 
Methods and Results: GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the alpha subunit of GC1 (GC alpha 1 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 alpha 1 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 GCa1 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: GC1 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.},
  articleno    = {e006397},
  author       = {Crassous, Pierre-Antoine and Shu, Ping and Huang, Can and Gordan, Richard and Brouckaert, Peter and Lampe, Paul D and Xie, Lai-Hua and Beuve, Annie},
  issn         = {2047-9980},
  journal      = {JOURNAL OF THE AMERICAN HEART ASSOCIATION},
  keywords     = {ACTIVATED INWARD CURRENT,SUDDEN ARRHYTHMIC DEATH,NITRIC-OXIDE,SYNTHASE,PROTEIN-KINASE I,HEART-RATE,MEMBRANE ASSOCIATION,SODIUM-CHANNELS,KNOCKOUT MICE,GAP-JUNCTIONS,UP-REGULATION,arrhythmia,cardiac function,cardiovascular disease,cGMP,connexin 43,guanylyl cyclase,Nitric oxide},
  language     = {eng},
  number       = {12},
  pages        = {21},
  title        = {Newly identified NO-sensor guanylyl cyclase/connexin 43 association is involved in cardiac electrical function},
  url          = {http://dx.doi.org/10.1161/JAHA.117.006397},
  volume       = {6},
  year         = {2017},
}

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