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.
"Confusingly, in vascular smooth muscle cells (VSMC) p21 was identified as a protein mediating an HO-1-dependent inhibition of proliferation, and antiproliferative potential of HO-1 was significantly reduced in VSMC obtained from p21 null mice . Additionally, treatment of wild-type VSMC with hemin downregulated the expression of cyclin-D1 and upregulated that of p21, the effects opposite to those observed in endothelium and many cancer cells . Similarly as in VSMC, the positive correlation of HO-1 and p21 was demonstrated in epithelial cells , papillary thyroid carcinoma , gastric cancer cell line , pancreatic , and hepatic stellate cells . "
[Show abstract][Hide abstract] ABSTRACT: Heme oxygenase-1 (HO-1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. As HO-1 expression is highly increased by stressful conditions, the major role of the enzyme is the protection against oxidative injury. Additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. Beneficial activities of HO-1 have been recognized in many pathological states e.g. atherosclerosis, diabetes, ischemia/reperfusion injury or organ transplantation. Interestingly HO-1 expression is very often boosted in tumor tissues and could be further elevated in response to radio-, chemo-, or photodynamic therapy. A growing body of evidence suggests that HO-1 may play a role in tumor induction and can potently improve the growth and spread of tumors. This review discusses the implications of HO-1 properties for tumor proliferation and cell death, differentiation, angiogenesis and metastasis, and tumor-related inflammation. Finally, it suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies.
Current drug targets 12/2010; 11(12):1551-70. DOI:10.2174/1389450111009011551 · 3.02 Impact Factor
"Aprotinin treatment significantly increased the fraction of cells in G1/G0 phases (Fig. 2B), down-regulated cyclin D, and upregulated p21. Interestingly, aprotinin treatment induced HO-1 protein in VSMC from SHR and reduced proliferation (Fig. 3B), consistent with our previous findings that hemininduced HO-1 expression reduced the proliferation of VSMC of SHR under inflammatory conditions (Jeon et al., 2009) such as hypertension. To confirm the effects of HO-1 directly, we transfected cells with mouse HO-1 DNA to specifically inhibit proliferation (Fig. 4C). "
[Show abstract][Hide abstract] ABSTRACT: Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.
Korean Journal of Physiology and Pharmacology 08/2009; 13(4):309-13. DOI:10.4196/kjpp.2009.13.4.309 · 1.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abnormal vascular smooth muscle cell (VSMC) proliferation is involved in the development of vascular diseases. However, the mechanisms by which insulin exerts this effect are not completely known. We hypothesize that microRNAs might be involved in insulin-induced VSMC proliferation.
VSMC proliferation was determined by [H]-thymidine incorporation; microRNAs were determined by microRNA chips and real-time PCR; and p21expression was determined by immunoblotting.
In this study, we found that insulin increased VSMC proliferation and miR-208 expression. Overexpression of miR-208 increased basal and insulin-mediated VSMC proliferation. Although a miR-208 inhibitor, by itself, had no effect on VSMC proliferation, it reduced the insulin-mediated cell proliferation. Moreover, miR-208 increased the transformation of cell cycle from G0/G1 phase to the S phase. Bioinformatics analysis found that p21, a member of the cyclin-dependent kinase (CDK)-inhibitory protein family, may be the target of miR-208. Insulin decreased p21 expression in VSMCs; transfection of miR-208 also decreased p21 protein expression. In the presence of miR-208 inhibitor, the inhibitory effect of insulin on p21 expression in VSMCs was partially blocked. The interaction between miR-208 and p21 was direct. Using a luciferase reporter with entire wild-type p21 3'UTR or a mutant p21 3'UTR in HEK293 cells, we found that miR-208 decreased but neither miR-208 mimic nor the mutant p21 3'UTR had any significant effect on the luciferase activity.
This study indicates that miRNAs, miR-208, in particular, are involved in the insulin-induced VSMC proliferation via downregulation of its potential target, p21, a key member of CDK-inhibitory protein family.
Journal of Hypertension 06/2011; 29(8):1560-8. DOI:10.1097/HJH.0b013e328348ef8e · 4.72 Impact Factor
Kuo-Yen Huang, Shih-Han Kao, Wen-Lung Wang, Chi-Yuan Chen, Tzu-Hung Hsiao, Santosh B Salunke, Jeremy J W Chen, Kang-Yi Su, Shuenn-Chen Yang, Tse-Ming Hong, Ching-Shih Chen, Pan-Chyr Yang,
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