TNF-alpha regulates vascular smooth muscle cell responses in genetic hypertension.
Cellular and molecular events in vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. SHR-derived VSMC showed increased proliferative capacity and MAP kinase levels in comparison with WKY-derived VSMC. Flow cytometry analysis revealed that progression from G1 to S phase was faster in SHR-derived VSMC in response to tumor necrosis factor-alpha (TNF-alpha) as compared with cells from WKY. The G1 cell cycle-associated proteins such as cyclin D1, cyclin E, CDK2 and CDK4, and kinase activities associated with CDK2 and CDK4, were increased in SHR-derived VSMC. In addition, CDK inhibitor p21 was elevated in SHR-derived cells. Matrix metalloproteinase-9 (MMP-9) expression and migration were also increased in response to TNF-alpha in SHR-derived cells. This increase was characterized by the up-regulation of MMP-9, which was transcriptionally regulated at the AP-1 and NF-kappaB sites in the MMP-9 promoter. These results suggest that the hypertensive-associated increase in VSMC proliferative capacity, G1 to S-phase cell-cycle progress and MMP-9 expression may play a role in vascular remodeling in hypertension.
Lee
Se-Jung
SJ
Department of Food and Biotechnology, Chungju National University, Chungju, Chungbuk 380-702, South Korea.
Kim
Wun-Jae
WJ
Moon
Sung-Kwon
SK
D000818:Animals; D001011:Aorta / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9