title: Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent.
abstract: OBJECTIVE
  The mitogen-activated protein (MAP) kinase system, especially the p38 MAP kinase, is activated in chronic heart failure (CHF). However, the role of vascular p38 MAP kinase in CHF has not been analyzed yet.
  
  
  RESULTS
  In aortic rings from rats with CHF 10 weeks after myocardial infarction, acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax: 54+/-5%) compared to sham-operated animals (Rmax: 77+/-5%, p<0.01), while endothelium-independent relaxation elicited by sodium nitroprusside was not significantly changed. Aortic levels of phosphorylated p38 MAP kinase protein were significantly elevated in rats with CHF. In addition, phosphorylation of MAP kinase-activated protein kinase-2 (MAPKAPK-2), an index of p38 MAP kinase activity, was increased. Aortic superoxide anion generation was significantly enhanced in rats with CHF accompanied by elevation of the NAD(P)H oxidase subunit p47phox protein expression. Inhibition of p38 MAP kinase by treatment with the p38 MAP kinase inhibitor SB239063 (800 ppm in standard rat chow) reduced MAPKAPK-2 phosphorylation, preserved acetylcholine-induced relaxation (Rmax: 80+/-4%, p<0.01), and reduced vascular superoxide formation. SB239063 treatment did not affect blood pressure and left ventricular enddiastolic pressure. In aortic tissue from CHF animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril, p38 MAP kinase phosphorylation was significantly reduced.
  
  
  CONCLUSIONS
  Vascular p38 MAP kinase is markedly activated in rats with CHF. Chronic p38 MAP kinase inhibition with SB239063 prevented endothelial vasomotor dysfunction through reduction of superoxide anion production.
authors.affiliation: Medizinische Klinik, Julius-Maximilians-Universität, Würzburg, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Widder
authors.forename: Thomas
authors.initials: T
authors.lastname: Behr
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Paolo
authors.initials: P
authors.lastname: Galuppo
authors.forename: Piet
authors.initials: P
authors.lastname: Tas
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Angermann
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D019255:NADPH Oxidases; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000109:Acetylcholine; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D019255:NADPH Oxidases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D013481:Superoxides; D014665:Vasodilator Agents; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C052035:trandolapril; C060505:neutrophil cytosolic factor 1; C406525:SB 239063