Pharmacogenetic Relevance of Endothelial Nitric Oxide Synthase Polymorphisms and Gene Interactions

Abstract

Endothelial nitric oxide synthase (NOS3) is a key enzyme responsible for nitric oxide (NO) generation in the vascular endothelium. Endothelial dysfunction is characterized by reduced NO production, and is a hallmark of cardiovascular diseases. Drugs with cardiovascular action may activate NOS3 and result in NO release and vasodilation. Moreover, genetic variations affect NOS3 expression and activity, and may partially explain the variability in the responses to cardiovascular drugs. We reviewed NO signaling and genetic effects on NO formation, and the effects of NOS3 polymorphisms, haplotypes and gene–gene interactions within NO signaling pathways on the responses to cardiovascular drugs. We discuss the role of rare NOS3 variants and further gene–gene interactions analysis for the development of novel therapies for cardiovascular diseases.

Keywords::

• endothelial nitric oxide synthase
• gene–gene interactions
• genetic polymorphisms
• haplotypes
• nitric oxide
• NOS3 gene
• pharmacogenetics

Financial & competing interests disclosure

This work was supported by grants from the National Council of Scientific and Technological Development (CNPq-Brazil) and the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP-Brazil). DA Pereira is supported by a fellowship of the Coordination of Improvement of Higher Level Personnel (CAPES-Brazil). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by grants from the National Council of Scientific and Technological Development (CNPq-Brazil) and the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP-Brazil). DA Pereira is supported by a fellowship of the Coordination of Improvement of Higher Level Personnel (CAPES-Brazil). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript