Blockade of TGF-β 1 signalling inhibits cardiac NADPH oxidase overactivity in hypertensive rats.
NADPH oxidases constitute a major source of superoxide anion (·O(2)(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-β 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-β 1 receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR) to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-β 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-β 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-β 1.
Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
José Luis
JL
Miguel-Carrasco
Ana
A
Baltanás
Carolina
C
Cebrián
María U
MU
Moreno
Begoña
B
López
Nerea
N
Hermida
Arantxa
A
González
Javier
J
Dotor
Francisco
F
Borrás-Cuesta
Javier
J
Díez
Ana
A
Fortuño
Guillermo
G
Zalba
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D018125:Receptors, Transforming Growth Factor beta / Q000627:therapeutic use; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D024042:Collagen Type I; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; C504795:TGF-beta1 type III receptor (730-743), human; D053773:Transforming Growth Factor beta1; C002744:3-nitrotyrosine; D014443:Tyrosine; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat