NAD(P)H oxidase and eNOS play differential roles in cytomegalovirus infection-induced microvascular dysfunction |
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Authors: | Leskov Igor L Whitsett Jennifer Vasquez-Vivar Jeannette Stokes Karen Y |
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Institution: | aDepartment of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA;bDepartment of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;cCenter for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA |
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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 gp91phox (NAD(P)H oxidase subunit) knockout mice received mock inoculum or 3 × 104 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), gp91phox 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 gp91phox 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. |
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Keywords: | Abbreviations: ACh acetylcholine BH4 tetrahydrobiopterin CMV cytomegalovirus eNOS endothelial nitric oxide synthase gp91phox&minus /&minus gp91phox knockout mice HC high-cholesterol diet L-NNA l-arginine" target="_blank">NG-nitro-l-arginine mCMV murine CMV ND normal diet O2&bull &minus superoxide ROS reactive oxygen species WT wild type |
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