Nitric oxide synthase-3 deficiency results in hypoplastic coronary arteries and postnatal myocardial infarction

Eur Heart J. 2014 Apr;35(14):920-31. doi: 10.1093/eurheartj/ehs306. Epub 2012 Oct 9.


Aims: Hypoplastic coronary artery disease is a rare congenital abnormality that is associated with sudden cardiac death. However, molecular mechanisms responsible for this disease are not clear. The aim of the present study was to assess the role of nitric oxide synthase-3 (NOS3) in the pathogenesis of hypoplastic coronary arteries.

Methods and results: Wild-type (WT), NOS3(-/-), and a novel cardiac-specific NOS3 overexpression mouse model were employed. Deficiency in NOS3 resulted in coronary artery hypoplasia in foetal mice and spontaneous myocardial infarction in postnatal hearts. Coronary artery diameters, vessel density, and volume were significantly decreased in NOS3(-/-) mice at postnatal day 0. In addition, NOS3(-/-) mice showed a significant increase in the ventricular wall thickness, myocardial volume, and cardiomyocyte cell size compared with WT mice. Lack of NOS3 also down-regulated the expression of Gata4, Wilms tumour-1, vascular endothelial growth factor, basic fibroblast growth factor and erythropoietin, and inhibited migration of epicardial cells. These abnormalities and hypoplastic coronary arteries in the NOS3(-/-) mice were completely rescued by the cardiac-specific overexpression of NOS3.

Conclusion: Nitric oxide synthase-3 is required for coronary artery development and deficiency in NOS3 leads to hypoplastic coronary arteries.

Keywords: Congenital heart disease; Coronary artery development; Nitric oxide synthase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Coronary Vessel Anomalies / embryology
  • Coronary Vessel Anomalies / enzymology*
  • Mice, Transgenic
  • Myocardial Infarction / embryology
  • Myocardial Infarction / enzymology*
  • Nitric Oxide Synthase Type III / deficiency*
  • Survival Analysis


  • Nitric Oxide Synthase Type III