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By High Glucose, Upregulate At, Receptor Expression, Potentiates Ang, Ii-induced Proliferation, Vsm Cells, Chhinder P. Sodhi, Yashpal S. Kanwar, Atul Sahai, Atul Sahai and Searle Bldg


We examined the effect of hypoxia and high glucose (HG) on Ang II type I (AT1) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Quiescent cells exposed to hypoxia in a serum-free DME/F12 medium for 6-24 hours induced a progressive increase in AT1 mRNA expression. Cells exposed to 24 hours of hypoxia also resulted in a significant increase in Ang II receptor binding as assessed with 125 I-labeled Ang II. Treatment with Ang II (1 µmol/l) for 24 hours under normoxic conditions caused ~ 1.5 fold increase in both DNA synthesis and cell number, which were enhanced to ~ 3.0 fold under hypoxic conditions. An AT1 receptor antagonist (losartan, 10 µmol/l) blocked the Ang II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mmol/l) for 12-24 hours under normoxic conditions induced ~ 2.5 fold increase in AT1 mRNA levels, which was markedly enhanced by hypoxia to ~ 5.5 fold at 12 hours and ~ 8.5 fold at 24 hours, respectively. Ang II under HG-normoxic conditions caused a complete down-regulation of AT1 expression, which was prevented by hypoxia. These results demonstrate an upregulation of AT1 receptor expression by hypoxia and HG in cultured VSM cells, and suggest a mechanism for enhanced Ang II-induced VSM cell proliferation and to the development of atherosclerosis in diabetes. 2 H-00625-2002R

Topics: Key Words, Vascular smooth muscle cells, diabetes, chronic hypoxia, cell growth, Ang II receptor
Year: 2013
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