Functional nitric oxide synthase mislocalization in cardiomyopathy

Ahlke Heydemann, Jill M. Huber, Rahul Kakkar, Matthew T. Wheeler, Elizabeth M. McNally*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Mutations in the dystrophin glycoprotein complex, and in particular the sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in γ-sarcoglycan or δ-sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.

Original languageEnglish (US)
Pages (from-to)213-223
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume36
Issue number2
DOIs
StatePublished - Jan 1 2004

Keywords

  • Animal models of human disease
  • Arrhythmias - basic studies
  • Endothelium/vascular type/nitric oxide
  • Genetically altered mice
  • Heart failure - basic studies

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Functional nitric oxide synthase mislocalization in cardiomyopathy'. Together they form a unique fingerprint.

Cite this