title: Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling.
abstract: OBJECTIVE
  Angiotensin II induces cardiac myocyte apoptosis and hypertrophy, which contribute to heart failure, possibly through enhanced oxidative stress. The aim of this work was to assess the impact of hemin (heme oxygenase-1 inducer) on NADPH oxidase activation, cardiac oxidative stress, and development of fibrosis in a rat model of renovascular hypertensive cardiomyopathy in comparison to an anti-hypertensive reference treatment with losartan.
  
  
  RESULTS
  A 3 week hemin treatment was tested in an angiotensin II-dependent hypertensive rat model and a cellular model of neonatal rat cardiomyocytes stimulated by angiotensin II. Our findings demonstrate that hemin prevented development of intercellular fibrosis, expression of collagen I, and disorganization of intracellular fibres. Oxidative stress and apoptosis evaluated in hypertensive myocardial tissue were decreased by hemin. The reference treatment with the angiotensin II receptor (AT(1)) antagonist (losartan) was less effective than hemin in prevention of fibrosis and oxidative stress, although it was more effective in reducing hypertension. Rac-1 activation and, subsequently, NADPH oxidase activity were further decreased with hemin than with losartan. Hemin enhanced the expression of phosphoinositide 3-kinase (PI3K) p85 regulatory subunit, in contrast to losartan. The PI3K/Akt signalling pathway activation by hemin was related to heme oxygenase-1 activation and an increase in biliverdin reductase, and its inhibition by LY294002 reversed the effects of hemin on collagen I and caspase-3 expression. Finally, hemin increased Akt activation, and concomitantly decreased RhoA and p38 mitogen-activated protein kinase activation.
  
  
  CONCLUSIONS
  We confirmed a positive effect of hemin on oxidative cardiac damage, apoptosis, and fibrosis induced by hypertension by modulating the NADPH oxidase activation through enhanced expression of the PI3K p85 regulatory subunit.
authors.affiliation: Labpart-EA3852, Faculté de Médecine, Université François Rabelais, Tours, France. morelelvis@yahoo.fr
authors.forename: Morel-Elvis
authors.initials: ME
authors.lastname: Worou
authors.forename: Karim
authors.initials: K
authors.lastname: Belmokhtar
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Patrick
authors.initials: P
authors.lastname: Vourc'h
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Machet
authors.forename: Georges
authors.initials: G
authors.lastname: Khamis
authors.forename: Véronique
authors.initials: V
authors.lastname: Eder
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005355:Fibrosis; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000975:Antioxidants; D024042:Collagen Type I; D000804:Angiotensin II; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D019808:Losartan