Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells.
We examined the effect of hypoxia and high glucose (HG) on ANG II type 1 (AT(1)) receptor expression and proliferation in cultured vascular smooth muscle (VSM) cells. Exposure of quiescent cells to hypoxia in a serum-free DME-Ham's F-12 medium for 6-24 h induced a progressive increase in AT(1) mRNA expression. Exposure of cells to 24 h 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 microM) for 24 h under normoxic conditions caused an approximately 1.5-fold increase in both DNA synthesis and cell number, which was enhanced to approximately 3.0-fold under hypoxic conditions. An AT(1) receptor antagonist (losartan, 10 microM) blocked the ANG II-induced increase in DNA synthesis under both normoxic and hypoxic conditions. Incubations in HG medium (25 mM) for 12-24 h under normoxic conditions induced an approximately 2.5-fold increase in AT(1) mRNA levels, which was markedly enhanced by hypoxia to approximately 5.5-fold at 12 h and approximately 8.5-fold at 24 h. ANG II under HG-normoxic conditions caused a complete downregulation of AT(1) expression, which was prevented by hypoxia. These results demonstrate an upregulation of AT(1) receptor expression by hypoxia and HG in cultured VSM cells and suggest a mechanism for enhanced ANG II-induced VSM cell proliferation and the development of atherosclerosis in diabetes.
Sodhi
Chhinder P
CP
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Kanwar
Yashpal S
YS
Sahai
Atul
A
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D005947:Glucose