Hemin inhibits hypertensive rat vascular smooth muscle cell proliferation through regulation of cyclin D and p21.
We tested the hypothesis that HO-1 (heme oxygenase-1) activity varied between vascular smooth muscle cells (VSMC) in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. HO-1 levels were measured under baseline and hemin-stimulated conditions and cell proliferation was monitored. Basal HO-1 levels in untreated cells were lower in SHR compared to WKY rats. Treatment with hemin increased HO-1 mRNA and protein levels in the cells obtained from WKY rats compared to that of SHR rats. However, hemin-treatment showed a greater inhibitory effect on VSMC proliferation in SHR rats than in WKY rats. Tin protoporphyrin IX (SnPPIX) showed a greater reversal of the anti-proliferative effect of hemin on cells from SHR rats than WKY. Similarly, VSMC proliferation from SHR was significantly inhibited in VSMC transfected with the HO-1 gene. These inhibitory effects were associated with cell cycle arrest in the G1 phase. The level of cyclin D, and cyclin dependent kinase inhibitor p21 was higher in SHR cells progressing through the G1 phase. Treatment of the cells with hemin down-regulated the expression of cyclin D and up-regulated that of p21. These results indicate that hemin, an HO-1 inducer, may play a more critical role in VSMC proliferation in SHR than WKY.
Jeon
Eun Mi
EM
Department of Pharmacology and Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, 705-717, Korea.
Choi
Hyoung Chul
HC
Lee
Kwang Youn
KY
Chang
Ki Churl
KC
Kang
Young Jin
YJ
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D014162:Transfection
C493958:Cdkn1a protein, rat; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D006427:Hemin; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat