Transforming growth factor‐β1 elicits Nrf2‐mediated antioxidant responses in aortic smooth muscle cells

The anti‐inflammatory properties of transforming growth factor‐β1 (TGF‐β1) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 (nuclear factor erythroid 2 [NF‐E2]‐related factor 2) transcription pathway is involved in TGF‐β1 mediated induction of the antioxidant enzyme heme oxygenase‐1 (HO‐1) in smooth muscle cells (SMC). Human aortic smooth muscle cells (HAoSMC) or wild‐type and Nrf2‐deficient mouse (MAoSMC) aortic SMC were treated with TGF‐β1 (2.5–10 ng/ml, 0–24 hrs). We report the first evidence that TGF‐β1 induces Nrf2 mediated HO‐1 expression and antioxidant response element activity, which was paralleled by enhanced superoxide production and expression of the NAD(P)H oxidase subunit p22phox. TGF‐β1 failed to induce HO‐1 expression in MAoSMC derived from Nrf2‐deficient mice, and HO‐1 induction by TGF‐β1 in HAoSMC was attenuated by inhibition of extracellular signal regulated kinase or c‐jun‐N‐terminal kinase but not p38 mitogen activated protein kinase. Inhibition of NAD(P)H oxidase or scavenging of superoxide diminished HO‐1 induction in response to TGF‐β1. The oxidative stress agents glucose oxidase (GOx) and diethylmaleate enhanced TGF‐β1 generation and HO‐1 expression in HAoSMC, while antagonism of TGF‐β1 signalling by adenoviral Smad7 overexpression attenuated their induction of HO‐1. Pre‐treatment of HAoSMC with TGF‐β1 reduced nuclear translocation of the pro‐apoptotic mediator p53 elicited by GOx. Our findings demonstrate that Nrf2 is a new target of TGF‐β1 signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.

[1]  R. Baron,et al.  p53 Brings a New Twist to the Smad Signaling Network , 2008, Science Signaling.

[2]  R. Linhardt,et al.  The role of the methoxyphenol apocynin, a vascular NADPH oxidase inhibitor, as a chemopreventative agent in the potential treatment of cardiovascular diseases. , 2008, Current vascular pharmacology.

[3]  Seong-Jin Kim,et al.  Smad7 sensitizes tumor necrosis factor induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappaB pathway. , 2007, Cancer research.

[4]  Hong Wang,et al.  Nitric oxide stimulates heme oxygenase-1 gene transcription via the Nrf2/ARE complex to promote vascular smooth muscle cell survival. , 2007, Cardiovascular research.

[5]  C. Ozaki.  Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms: A First Approach to Induction of Functional Healing by Endovascular Gene Therapy , 2007 .

[6]  Keith K. Fenrich,et al.  Protection of Human Vascular Smooth Muscle Cells From H2O2-Induced Apoptosis Through Functional Codependence Between HO-1 and AKT , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[7]  M. Yen,et al.  Heme oxygenase-1 contributes to the cytoprotection of alpha-lipoic acid via activation of p44/42 mitogen-activated protein kinase in vascular smooth muscle cells. , 2006, Free radical biology & medicine.

[8]  D. Bull,et al.  Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[9]  A. Kong,et al.  Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. , 2006, Antioxidants & redox signaling.

[10]  S. Reddy,et al.  Nrf2 defends the lung from oxidative stress. , 2006, Antioxidants & redox signaling.

[11]  Satoru Takahashi,et al.  Redox Imbalance in Cystine/Glutamate Transporter-deficient Mice* , 2005, Journal of Biological Chemistry.

[12]  D. Sorescu,et al.  NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-β1–Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts , 2005, Circulation research.

[13]  K. Sharma,et al.  Reactive oxygen species production via NADPH oxidase mediates TGF-beta-induced cytoskeletal alterations in endothelial cells. , 2005, American journal of physiology. Renal physiology.

[14]  S. R. Grant,et al.  Transforming Growth Factor-β1-induced Expression of Smooth Muscle Marker Genes Involves Activation of PKN and p38 MAPK* , 2005, Journal of Biological Chemistry.

[15]  A. Mauviel,et al.  Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis , 2005, Oncogene.

[16]  P. Desgranges,et al.  Overexpression of Transforming Growth Factor-&bgr;1 Stabilizes Already-Formed Aortic Aneurysms: A First Approach to Induction of Functional Healing by Endovascular Gene Therapy , 2005, Circulation.

[17]  F. Bach,et al.  Heme oxygenase‐1: a therapeutic amplification funnel , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  G. Mann,et al.  Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2. , 2005, Free radical biology & medicine.

[19]  Jiang Li,et al.  The hypothesis , 1990 .

[20]  P. Weissberg,et al.  Smad7 Gene Transfer Attenuates Adventitial Cell Migration and Vascular Remodeling After Balloon Injury , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[21]  S. Uh,et al.  Role of Reactive Oxygen Species in TGF-β1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells , 2005 .

[22]  C. Arteaga,et al.  Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. , 2005, Free radical biology & medicine.

[23]  J. Westwick,et al.  SMAD and p38 MAPK Signaling Pathways Independently Regulate α1(I) Collagen Gene Expression in Unstimulated and Transforming Growth Factor-β-stimulated Hepatic Stellate Cells* , 2005, Journal of Biological Chemistry.

[24]  T. Suga,et al.  c-Src and Hydrogen Peroxide Mediate Transforming Growth Factor-β1–Induced Smooth Muscle Cell–Gene Expression in 10T1/2 Cells , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[25]  K. Griendling,et al.  Functional association of nox1 with p22phox in vascular smooth muscle cells. , 2004, Free radical biology & medicine.

[26]  M. Di Nisio,et al.  Increased Expression of Transforming Growth Factor-β1 as a Stabilizing Factor in Human Atherosclerotic Plaques , 2004, Stroke.

[27]  E. Bramucci,et al.  Different Quantitative Apoptotic Traits in Coronary Atherosclerotic Plaques From Patients With Stable Angina Pectoris and Acute Coronary Syndromes , 2004, Circulation.

[28]  C. Song,et al.  Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells. , 2004, Biochemical and biophysical research communications.

[29]  D. Dorscheid,et al.  Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-beta1 in human airway epithelial cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[30]  K. Itoh,et al.  Downloaded from http://circres.ahajournals.org / by guest on February 23, 2013Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages Activation by Oxidatively Modified LDL and 4-Hydroxynonenal , 2004 .

[31]  D. Grainger,et al.  Transforming growth factor , 2003 .

[32]  A. Daiber,et al.  Measurement of NAD(P)H oxidase-derived superoxide with the luminol analogue L-012. , 2004, Free radical biology & medicine.

[33]  C. B. Pickett,et al.  Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. , 2003, Annual review of pharmacology and toxicology.

[34]  G. FitzGerald,et al.  Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS , 2003, Circulation.

[35]  N. Bodyak,et al.  Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury , 2003, Nature Medicine.

[36]  G. Mann,et al.  Vitamin C inhibits diethylmaleate-induced L-cystine transport in human vascular smooth muscle cells. , 2003, Free radical biology & medicine.

[37]  Solomon H. Snyder,et al.  Biliverdin reductase: A major physiologic cytoprotectant , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Hongyu Wang,et al.  Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression* , 2002, The Journal of Biological Chemistry.

[39]  Mary E. Choi,et al.  TGF-β1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells , 2002 .

[40]  S. Chakraborty,et al.  Reaction of Reduced Flavins and Flavoproteins with Diphenyliodonium Chloride* , 2002, The Journal of Biological Chemistry.

[41]  K. Channon.  Oxidative stress and coronary plaque stability. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[42]  N. Deshpande,et al.  Mechanism of hydrogen peroxide-induced cell cycle arrest in vascular smooth muscle. , 2002, Antioxidants & redox signaling.

[43]  A. Tedgui,et al.  The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives , 2002, Current opinion in lipidology.

[44]  M. Daemen,et al.  Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[45]  Jeffrey L. Wrana,et al.  Signal Transduction by the TGF-β Superfamily , 2002, Science.

[46]  R. Busse,et al.  NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells , 2002, Circulation.

[47]  S. Shyue,et al.  Adenovirus-Mediated Heme Oxygenase-1 Gene Transfer Inhibits the Development of Print , 2001 .

[48]  D. Harrison,et al.  Electron spin resonance characterization of the NAD(P)H oxidase in vascular smooth muscle cells. , 2001, Free radical biology & medicine.

[49]  F. Lallemand,et al.  Smad7 inhibits the survival nuclear factor κB and potentiates apoptosis in epithelial cells , 2001, Oncogene.

[50]  F. Ziyadeh,et al.  Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. , 2001, Kidney international.

[51]  H. Nick,et al.  Smad7-dependent Regulation of Heme Oxygenase-1 by Transforming Growth Factor-β in Human Renal Epithelial Cells* , 2000, The Journal of Biological Chemistry.

[52]  Y. Mo,et al.  Activation of Mitogen-activated Protein Kinase Pathways Induces Antioxidant Response Element-mediated Gene Expression via a Nrf2-dependent Mechanism* , 2000, The Journal of Biological Chemistry.

[53]  R. Virmani,et al.  The good smooth muscle cells in atherosclerosis , 2000, Current atherosclerosis reports.

[54]  R. Busse,et al.  Oxidative stress and expression of p22phox are involved in the up‐regulation of tissue factor in vascular smooth muscle cells in response to activated platelets , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  T. McCaffrey.  TGF-s and TGF- receptors in atherosclerosis , 2000 .

[56]  A. Choi,et al.  Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway , 2000, Nature Medicine.

[57]  D. Sorescu,et al.  NAD(P)H oxidase: role in cardiovascular biology and disease. , 2000, Circulation research.

[58]  K. Jan,et al.  NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. , 2000, Circulation research.

[59]  G. Wahl,et al.  p53 regulation by post-translational modification and nuclear retention in response to diverse stresses , 1999, Oncogene.

[60]  R. von Harsdorf,et al.  p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c‐independent apoptosis blocked by Bcl‐2 , 1999, The EMBO journal.

[61]  G. Mann,et al.  Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? , 1999, Cardiovascular research.

[62]  P. Sarathchandra,et al.  Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase‐1 , 1998, British journal of pharmacology.

[63]  Tzong-Shyuan Lee,et al.  Expression of heme oxygenase-1 in atherosclerotic lesions. , 1998, The American journal of pathology.

[64]  R. Dietz,et al.  Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells. , 1997, Circulation.

[65]  C. Heldin,et al.  Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling , 1997, Nature.

[66]  M. Maines,et al.  The heme oxygenase system: a regulator of second messenger gases. , 1997, Annual review of pharmacology and toxicology.

[67]  T. Ishii,et al.  Cystine uptake and glutathione level in endothelial cells exposed to oxidative stress. , 1992, The American journal of physiology.