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NAD(P)H oxidase and eNOS play differential roles in cytomegalovirus infection-induced microvascular dysfunction. Free Radic Biol Med 2011 Dec 15;51(12):2300-8

Date

10/29/2011

Pubmed ID

22033010

Pubmed Central ID

PMC3272703

DOI

10.1016/j.freeradbiomed.2011.09.039

Abstract

Primary cytomegalovirus (CMV) infection promotes oxidative stress and reduces nitric oxide (NO) bioavailability in endothelial cells. These events are among the earliest vascular responses to cardiovascular risk factors. We assessed the roles of NAD(P)H oxidase and NO bioavailability in microvascular responses to persistent CMV infection alone or with hypercholesterolemia. Wild-type (WT) or gp91(phox) (NAD(P)H oxidase subunit) knockout mice received mock inoculum or 3×10(4) PFU murine CMV (mCMV) ip 5 weeks before placement on a normal or high-cholesterol diet (HC) for 4 weeks before assessment of arteriolar function and venular blood cell recruitment using intravital microscopy. Some WT groups received sepiapterin (a precursor of the nitric oxide synthase cofactor tetrahydrobiopterin) or apocynin (NAD(P)H oxidase inhibitor/antioxidant). Endothelium-dependent vasodilation was impaired in mCMV vs mock WT, regardless of diet. This was not affected by sepiapterin, and pharmacological inhibition of nitric oxide synthase reduced dilation similarly in mock and mCMV mice. Apocynin or deficiency of total, but not blood cell or vascular wall only (tested using bone marrow chimeras), gp91(phox) protected against arteriolar dysfunction. Blood cell recruitment was induced by mCMV-HC. Sepiapterin, but not NAD(P)H oxidase deficiency/apocynin, reduced leukocyte accumulation, whereas platelet adhesion was reduced by sepiapterin, apocynin, or total, platelet-specific, or vascular wall gp91(phox) deficiency. These data implicate activation of both hematopoietic and vessel wall NAD(P)H oxidase in mCMV-induced arteriolar dysfunction and platelet and vascular NAD(P)H oxidase in the thrombogenic phenotype induced by mCMV-HC. In contrast, findings with sepiapterin suggest that eNOS dysfunction, perhaps uncoupling, mediates venular, but not arteriolar, responses to mCMV-HC, thus indicating that NAD(P)H oxidase and eNOS differentially regulate microvascular responses to mCMV.

Author List

Leskov IL, Whitsett J, Vasquez-Vivar J, Stokes KY

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cytomegalovirus
Cytomegalovirus Infections
Mice
Mice, Congenic
Mice, Inbred C57BL
Mice, Knockout
Microvessels
NADPH Oxidases
Nitric Oxide Synthase Type III
Receptors, Immunologic
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2