Enhanced cell cycle entry and mitogen-activated protein kinase-signaling and downregulation of matrix metalloproteinase-1 and -3 in human diabetic arterial vasculature.
Diabetic patients have a strong predilection for atherosclerosis and postangioplasty restenosis. Accelerated cell proliferation and excessive extracellular matrix deposition are believed to contribute to the development of atherosclerotic plaques and neointima. We investigated the effect of diabetes on cell cycle, proliferation signaling, and the activation of matrix metalloproteinases (MMPs). Segments of internal mammary arteries from 26 type 2 diabetic and 26 non-diabetic patients undergoing coronary artery bypass grafting surgery were compared. Increased levels of cyclin D1 mRNA (by 135+/-14%) and protein expression (by 93.8+/-7.0%), retinoblastoma protein phosphorylation (by 45.9+/-4.8%), and beta-catenin nuclear localization (by 176+/-16%) indicated the enhanced cell cycle entry in the diabetic arteries. Diabetes increased phosphorylation of extracellular signal-regulated kinase-1/2 and p-38-mitogen-activated protein kinase (MAPK) by 76.0+/-6.8 and 62.3+/-4.3%. Increased collagen deposition was evidenced in the diabetic arteries. mRNA levels of MMP-1 and MMP-3 were decreased in the diabetic tissue to 55 and 82%, respectively, compared to the non-diabetic group; protein levels were also decreased accompanied with decreased enzymatic activities by 21 and 50%, respectively. In conclusion, enhanced cell cycle entry, increased MAPK signaling, and downregulated MMP-1 and MMP-3 were characteristic of diabetic arterial vasculature, and could contribute to the progressive atherosclerosis and postangioplasty restenosis in diabetic patients.
Chung
Ada W Y
AW
The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St. Paul's Hospital, Canada. achung@mrl.ubc.ca
Luo
Honglin
H
Tejerina
Teresa
T
van Breemen
Cornelis
C
Okon
Elena B
EB
D000368:Aged; D017130:Angioplasty / Q000009:adverse effects; D001158:Arteries / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D048909:Diabetes Complications / Q000209:etiology*; D003920:Diabetes Mellitus / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008875:Middle Aged; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019938:Cyclin D1; D048051:p38 Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1