Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats.

Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg(-1)·day(-1), 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2 (·-) production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.

[1]  Q. Su,et al.  Pioglitazone enhances the blood pressure-lowering effect of losartan via synergistic attenuation of angiotensin II-induced vasoconstriction , 2014, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[2]  M. Barančík,et al.  Effects of PPARγ Agonist Pioglitazone on Redox-Sensitive Cellular Signaling in Young Spontaneously Hypertensive Rats , 2013, PPAR research.

[3]  R. Nagai,et al.  Pioglitazone ameliorates systolic and diastolic cardiac dysfunction in rat model of angiotensin II-induced hypertension. , 2013, International journal of cardiology.

[4]  J. Redondo,et al.  Reciprocal relationship between reactive oxygen species and cyclooxygenase-2 and vascular dysfunction in hypertension. , 2013, Antioxidants & redox signaling.

[5]  M. Yanagisawa,et al.  ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy. , 2012, Life sciences.

[6]  A. Briones,et al.  Pioglitazone treatment increases COX‐2‐derived prostacyclin production and reduces oxidative stress in hypertensive rats: role in vascular function , 2012, British journal of pharmacology.

[7]  Y.-Y. Du,et al.  Pioglitazone induces regression and stabilization of coronary atherosclerotic plaques in patients with impaired glucose tolerance , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[8]  E. Schiffrin,et al.  Endothelin in hypertension: an update , 2012, Current opinion in nephrology and hypertension.

[9]  A. Briones,et al.  Peroxisome proliferator-activated receptor-&ggr; activation reduces cyclooxygenase-2 expression in vascular smooth muscle cells from hypertensive rats by interfering with oxidative stress , 2012, Journal of hypertension.

[10]  J. Tamargo,et al.  Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension. , 2012, Free radical biology & medicine.

[11]  J. Pollock,et al.  ETA activation mediates angiotensin II-induced infiltration of renal cortical T cells. , 2011, Journal of the American Society of Nephrology : JASN.

[12]  David Lagares,et al.  Role of endothelin in the cardiovascular system. , 2011, Pharmacological research.

[13]  L. Stow,et al.  Endothelin‐1 gene regulation , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  Steven J Brown,et al.  A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells. , 2010, ACS chemical biology.

[15]  M. Simionescu,et al.  Transcriptional regulation of NADPH oxidase isoforms, Nox1 and Nox4, by nuclear factor-kappaB in human aortic smooth muscle cells. , 2010, Biochemical and biophysical research communications.

[16]  J. Chan,et al.  Oral Intake of Rosiglitazone Promotes a Central Antihypertensive Effect Via Upregulation of Peroxisome Proliferator-Activated Receptor-&ggr; and Alleviation of Oxidative Stress in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats , 2010, Hypertension.

[17]  A. Knox,et al.  Endothelin-1 (ET-1) Increases the Expression of Remodeling Genes in Vascular Smooth Muscle through Linked Calcium and cAMP Pathways , 2010, The Journal of Biological Chemistry.

[18]  Chuanqin Fang,et al.  Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension* , 2010, The Journal of Biological Chemistry.

[19]  Yen-Ling Chen,et al.  Uric acid activates extracellular signal-regulated kinases and thereafter endothelin-1 expression in rat cardiac fibroblasts. , 2010, International journal of cardiology.

[20]  B. Yin,et al.  Downregulating osteopontin reduces angiotensin II-induced inflammatory activation in vascular smooth muscle cells , 2009, Inflammation Research.

[21]  A. Briones,et al.  p38 MAPK contributes to angiotensin II-induced COX-2 expression in aortic fibroblasts from normotensive and hypertensive rats , 2009, Journal of hypertension.

[22]  D. Harrison,et al.  Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. , 2008, Free radical biology & medicine.

[23]  C. Yabe-Nishimura,et al.  The AP-1 site is essential for the promoter activity of NOX1/NADPH oxidase, a vascular superoxide-producing enzyme: Possible involvement of the ERK1/2-JunB pathway. , 2008, Biochemical and biophysical research communications.

[24]  M. Yanagisawa,et al.  Endothelin: 20 years from discovery to therapy. , 2008, Canadian journal of physiology and pharmacology.

[25]  M. Simionescu,et al.  AP-1–Dependent Transcriptional Regulation of NADPH Oxidase in Human Aortic Smooth Muscle Cells: Role of p22phox Subunit , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[26]  K. Kamata,et al.  Relationships among ET-1, PPARγ, oxidative stress and endothelial dysfunction in diabetic animals(Hirosi Kuriyama Award 2007 Memorial Review) , 2008 .

[27]  K. Kamata,et al.  Relationships among ET-1, PPARgamma, oxidative stress and endothelial dysfunction in diabetic animals. , 2008, Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi.

[28]  A. Briones,et al.  Role of NADPH oxidase and iNOS in vasoconstrictor responses of vessels from hypertensive and normotensive rats , 2008, British journal of pharmacology.

[29]  D. Pearse,et al.  Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species. , 2008, American journal of physiology. Renal physiology.

[30]  Ling-Yun Wu,et al.  PEROXISOME PROLIFERATOR‐ACTIVATED RECEPTOR‐γ AGONISTS ATTENUATE ANGIOTENSIN II‐INDUCED COLLAGEN TYPE I EXPRESSION IN ADVENTITIAL FIBROBLASTS , 2008, Clinical and experimental pharmacology & physiology.

[31]  C. Glass,et al.  PPARs and molecular mechanisms of transrepression. , 2007, Biochimica et biophysica acta.

[32]  A. Briones,et al.  Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats , 2007, Journal of Pharmacology and Experimental Therapeutics.

[33]  K. Kamata,et al.  Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats. , 2007, Free radical biology & medicine.

[34]  E. Schiffrin,et al.  Inhibitory effects of PPAR-gamma on endothelin-1-induced inflammatory pathways in vascular smooth muscle cells from normotensive and hypertensive rats. , 2007, Journal of the American Society of Hypertension : JASH.

[35]  M. Quon,et al.  Treatment of Spontaneously Hypertensive Rats With Rosiglitazone and/or Enalapril Restores Balance Between Vasodilator and Vasoconstrictor Actions of Insulin With Simultaneous Improvement in Hypertension and Insulin Resistance , 2006, Diabetes.

[36]  E. Schiffrin,et al.  Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. , 2006, Vascular pharmacology.

[37]  Marta Ruiz-Ortega,et al.  Renal and vascular hypertension-induced inflammation: role of angiotensin II , 2006, Current opinion in nephrology and hypertension.

[38]  C. Thiemermann,et al.  Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. , 2006, European journal of pharmacology.

[39]  M. Sánchez-Hidalgo,et al.  Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats. , 2005, Biochemical pharmacology.

[40]  A. Briones,et al.  Hypertension increases the participation of vasoconstrictor prostanoids from cyclooxygenase-2 in phenylephrine responses , 2005, Journal of hypertension.

[41]  R. Wu,et al.  Endothelin mediates superoxide production in angiotensin II-induced hypertension in rats. , 2005, Free radical biology & medicine.

[42]  Y. Surh,et al.  Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. , 2004, Biochemical pharmacology.

[43]  N. Chang,et al.  Role of Reactive Oxygen Species-Sensitive Extracellular Signal-Regulated Kinase Pathway in Angiotensin II-Induced Endothelin-1 Gene Expression in Vascular Endothelial Cells , 2004, Journal of Vascular Research.

[44]  Jaung-Geng Lin,et al.  Angiotensin II induces endothelin-1 gene expression via extracellular signal-regulated kinase pathway in rat aortic smooth muscle cells. , 2004, Cardiovascular research.

[45]  T. Cheng,et al.  Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts. , 2003, Journal of the American College of Cardiology.

[46]  E. Araki,et al.  Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. , 2003, Diabetes.

[47]  L. Musiari,et al.  Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans , 2003, Hypertension.

[48]  I. Yamaguchi,et al.  Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats. , 2002, Clinical science.

[49]  E. Schiffrin,et al.  Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II–Infused Rats: Role of Peroxisome Proliferator–Activated Receptor-&ggr; , 2002, Circulation.

[50]  S. Boyault,et al.  PPAR-γ ligands modulate effects of LPS in stimulated rat synovial fibroblasts , 2002 .

[51]  J. Egido,et al.  Angiotensin II activates nuclear transcription factor-kappaB in aorta of normal rats and in vascular smooth muscle cells of AT1 knockout mice. , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[52]  K. Subbaramaiah,et al.  Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. , 2001, The Journal of biological chemistry.

[53]  P. Fasching,et al.  Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. , 2000, Diabetes.

[54]  A. Pessina,et al.  Interactions between endothelin-1 and the renin–angiotensin–aldosterone system , 1999 .

[55]  S. Rajagopalan,et al.  Role for endothelin-1 in angiotensin II-mediated hypertension. , 1997, Hypertension.

[56]  Y. Xia,et al.  Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. , 1995, The Journal of clinical investigation.

[57]  H. Kawasaki,et al.  Inhibition of plasma endothelin-1 concentration by captopril in patients with essential hypertension. , 1994, Clinical nephrology.

[58]  今井 泰平 Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells , 1993 .

[59]  T. Resink,et al.  Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. , 1990, Cell regulation.

[60]  D. Hwang,et al.  Involvement of Reactive Oxygen Intermediates in Cyclooxygenase-2 Expression Induced by Interleukin-1 , Tumor Necrosis Factor-a , and Lipopolysaccharide , 2022 .