Overexpression of heme oxygenase-1 protects smooth muscle cells against oxidative injury and inhibits cell proliferation

Zhang, Min; Zhang, Bao Hui; Chen, Li; An, Wei

doi:10.1038/sj.cr.7290118

Cited by 87 publications

(60 citation statements)

References 32 publications

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“…These data are important because HO-1 is known to have widespread effects on cellular proliferation. Most commonly, HO-1 induction leads to decreased growth and inhibition of vascular (Zhang et al 2002) and tracheal smooth muscle proliferation (Taille et al 2003). Induction or overexpression of HO-1 also reduces proliferation in kidney and pulmonary epithelial cells (Aizawa et al 2001;Lee et al 1996), which are findings consistent with the increased proliferation of hepatocytes that express core protein.…”

Section: Discussionmentioning

confidence: 71%

Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

et al. 2007

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Hepatitis C virus (HCV) core protein is a transcriptional modifier whose expression is associated with increased levels of prooxidants in hepatocytes in vivo and in vitro. We previously reported that HCV-infected liver biopsies and core protein-expressing hepatocytes show diminished levels of heme oxygenase-1 (HO-1), which is an important oxidative defense enzyme. The objective of these studies was to test the hypothesis that the expression of core protein sensitizes hepatocytes to toxic injury and inhibits the induction of HO-1 in response to stress. The effects of core protein were tested in two different human hepatocyte cell lines, HepG2 and Huh7, which show increased prooxidative activity and cytotoxicity after treatment with heme, heavy metals, and peroxides compared to control cells. HO-1 is upregulated in response to these treatments in control cells, while the induction is attenuated in core protein-expressing cells. The effects of core protein on HO-1 expression are not accounted for by differences in HO-1 mRNA turnover or by the known effects of core protein on cellular proliferation. Collectively, these data suggest that HCV core protein may contribute to hepatocellular injury by increasing both steady-state levels of prooxidants and the susceptibility of hepatocytes to damage by impairing their response to other sources of oxidative stress.

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Section: Discussionmentioning

confidence: 71%

Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

et al. 2007

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“…10,50 This is most commonly attributed to CO production, 30,36 although bilirubin/biliverdin have also been reported to inhibit VSMC growth. 51 In VSMCs, CO can activate soluble guanylate cyclase, leading to increased cGMP, 52 activation of p38 MAPK, and induction of the cell cycle inhibitor p21 Waf1/Cip1 .…”

Section: Beck Et Al Interplay Between Ho-1 and Yy1mentioning

confidence: 99%

Interplay Between Heme Oxygenase-1 and the Multifunctional Transcription Factor Yin Yang 1 in the Inhibition of Intimal Hyperplasia

Beck

et al. 2010

Circulation Research

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Objective: Because such cell-specific effects are reminiscent of the action of the transcription factor Yin Yang (YY)1, we tested the hypothesis that there is a functional relationship between HO-1 and YY1. Methods and Results: We report that probucol increases the number of YY1؉ cells in rat carotid artery following balloon injury at a time coinciding with increased HO-1 expression. The drug also induces the expression of YY1 mRNA and protein in rat aortic smooth muscle cells (RASMCs) in vitro, as do other known HO-1 inducers (tert-butylhydroquinone and hemin) and overexpression of HO-1 using a human HMOX1 cDNA plasmid. Conversely, overexpression of YY1 induces expression of HO-1 in RASMCs. Induction of YY1 expression is dependent on HO-1 enzyme activity and its reaction product CO, because pharmacological inhibition of heme oxygenase activity or CO scavenging block, whereas exposure of RASMCs to a CO-releasing molecule increases, YY1 expression. Furthermore, RNA interference knockdown of YY1 prevents probucol or adeno-HO-1 from inhibiting RASMC proliferation in vitro and neointimal formation in vivo. Key Words: Heme oxygenase-1 Ⅲ smooth muscle cell proliferation Ⅲ YY1 Ⅲ carbon monoxide Ⅲ probucol A therosclerotic vascular disease is the leading cause of mortality in the Western world. Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after angioplasty or stenting. 1 Agents that inhibit the proliferation of VSMCs are of considerable therapeutic importance for the treatment of cardiovascular diseases. This is particularly the case for in-stent restenosis, the incidence of which has been reduced dramatically by the widespread use of stents that elute cell proliferation-inhibitory drugs. However, the incidence of in-stent thrombosis remains a significant clinical problem 2 given the potentially life threatening consequences of a thrombotic event. The endothelium plays a crucial role in the prevention of in-stent thrombosis, with delayed reendothelialization likely responsible for late stent thrombosis. 3 Most conventional, orally administered, drugs have failed to inhibit restenosis in humans following coronary angioplasty and stenting, 4 -6 one exception being probucol, a rarely used lipid-lowering drug with antiinflammatory and antioxidant properties. 7 Probucol has also been reported to inhibit experimental in-stent thrombosis. 8 These beneficial effects are associated with promotion of endothelial cell growth and enhancement of reendothelialization and inhibition of VSMC proliferation. 9 Recent evidence suggests that the mechanisms of probucol and related compounds to inhibit VSMC proliferation, as well as experimental restenosis and atherosclerosis, are mediated via induction of the enzyme heme oxygenase (HO)-1. 10,11 HO-1 is the inducible of 2 forms of heme oxygenases that degrade heme to CO, Fe 2ϩ , and biliverdin, which is then The HO-1-induced opposing effect on the growth of VSMCs versus endothelial cells is reminiscent of the effect...

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“…Antioxidant proteins have important protective roles against VSMC migration and neointima formation after vascular injury through antioxidative stress (15,24,39). We investigated the effect of PGC-1␣ on the expression of the following oxidative stress protective proteins cytoplasmic SOD-1 (or Cu/ZnSOD), mitochondrial SOD-2 (or MnSOD), microsomal HO-1, and cytoplasmic Trx-1.…”

Section: Pgc-1␣ Increased the Basal Expression Of Antioxidant Proteinmentioning

confidence: 99%

PGC-1α attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery

Jiang

et al. 2009

American Journal of Physiology-Cell Physiology

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X. PGC-1␣ attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery. Am J Physiol Cell Physiol 297: C645-C653, 2009. First published June 24, 2009 doi:10.1152/ajpcell.00469.2008.-Oxidative stress contributes significantly to the migration of vascular smooth muscle cells (VSMCs), the major pathogenic process of vascular diseases, but the mechanism remains unclear. In the present study, we explored the role of peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), a major regulator of mitochondrial biogenesis and energy balance, in VSMC migration in vitro and in vivo. Overexpression of PGC-1␣ in cultured VSMCs led to a 74.5% reduction of migration activity and mitochondrial ROS generation by the increased expression of antioxidative proteins such as SOD-2 in the mitochondria. The knockdown of PGC-1␣ by specific small interfering (si)RNA markedly augmented VSMC migration activity and greatly reduced mitochondrial antioxidative protein expression. Furthermore, knockdown of SOD-2 expression by siRNA greatly reversed the inhibitory effect of PGC-1␣ overexpression on VSMC migration. In a rat carotid balloon injury model, adenovirus-mediated overexpression of PGC-1␣ greatly reduced neointimal formation (ratio of intima to media: 0.78 Ϯ 0.09 vs. 1.45 Ϯ 0.18 in the adenovirus ϩ green fluorescent protein genetransfected group). Moreover, the expression of SOD-2 was significantly increased in vivo in local vessels after injury in the PGC-1␣-overexpressing group. These data strongly suggest that PGC-1␣ inhibits VSMC migration and neointimal formation after vascular injury in rats, mainly by upregulating the expression of the mitochondrial antioxidant enzyme SOD-2. restenosis; antioxidants; smooth muscle cells; metabolic syndrome; peroxisome proliferator-activated receptor-␥ coactivator-1␣ VASCULAR SMOOTH MUSCLE CELL (VSMC) proliferation and migration are characteristic features of various vascular diseases such as atherosclerosis and neointimal hyperplasia after vascular intervention (6,28). Increased oxidative stress in VSMCs plays an important role in the pathogenesis of atherosclerosis and neointima formation (3,20). Genetic and pharmacological inhibition of ROS-generating systems can ameliorate atherosclerosis and neointimal hyperplasia after vascular injury in animal models (20,34).Peroxisome proliferator-activated receptor (PPAR)-␥ coactivator (PGC)-1␣, originally identified as a transcriptional coactivator of PPAR-␥ (30), is a central regulator of lipid catabolism and mitochondrial number and function (9). PGC-1␣ is abundantly expressed in tissues and cells with high metabolic rates, such as brown adipose tissue (35), skeletal muscle (7,23,25), the liver (33), the heart (2), and the brain (11). Our studies and those of others have demonstrated that PGC-1␣ is also expressed in vascular cells, especially in VSMCs (17, 40) and endothelial cells (ECs) (17,36), but the role of PGC-1␣ in vascular cells remains ambiguous. We have previously demon...

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Overexpression of heme oxygenase-1 protects smooth muscle cells against oxidative injury and inhibits cell proliferation

Cited by 87 publications

References 32 publications

Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

Interplay Between Heme Oxygenase-1 and the Multifunctional Transcription Factor Yin Yang 1 in the Inhibition of Intimal Hyperplasia

PGC-1α attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery

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