Thrombin and NAD(P)H oxidase-mediated regulation of CD44 and BMP4-Id pathway in VSMC, restenosis, and atherosclerosis.
To characterize novel signaling pathways that underlie NAD(P)H oxidase-mediated signaling in atherosclerosis, we first examined differences in thrombin-induced gene expression between wild-type and p47phox(-/-) (NAD[P]H oxidase-deficient) VSMC. Of the 9000 genes analyzed by cDNA microarray method at the G1/S transition point, 76 genes were similarly and significantly modulated in both the cell types, whereas another 22 genes that encompass various functional groups were regulated in NAD(P)H oxidase-dependent manner. Among these 22 genes, thrombin-induced NAD(P)H oxidase-mediated regulation of Klf15, Igbp1, Ak4, Adamts5, Ech1, Serp1, Sec61a2, Aox1, Aoh1, Fxyd5, Rai14, and Serpinh1 was shown for the first time in VSMC. The role of NAD(P)H oxidase in the regulation of a subset of these genes (CD44, BMP4, Id1, and Id3) was confirmed using modulators of reactive oxygen species (ROS) generation, a ROS scavenger and in gain-of-function experiments. We then characterized regulation of these genes in restenosis and atherosclerosis. In both apoE(-/-) mice and in a mouse vascular injury model, these genes are regulated in NAD(P)H oxidase-dependent manner during vascular lesion formation. Based on these findings, we propose that NAD(P)H oxidase-dependent gene expression in general, and the CD44 and BMP4-Id signaling pathway in particular, is important in restenosis and atherosclerosis.
Vendrov
Aleksandr E
AE
Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-7055, USA.
Madamanchi
Nageswara R
NR
Hakim
Zeenat S
ZS
Rojas
Mauricio
M
Runge
Marschall S
MS
D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D005263:Femoral Artery / Q000293:injuries; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006965:Hyperplasia; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000502:physiology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013917:Thrombin / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D014947:Wounds and Injuries / Q000473:pathology
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018960:Hyaluronan Receptors; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D017382:Reactive Oxygen Species; C067679:Idb3 protein, mouse; D019255:NADPH Oxidases; D013917:Thrombin