Prevention of aortic fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in angiotensin II-induced hypertension.
Fibrosis is an important component of large conduit artery disease in hypertension. The endogenous tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory and antifibrotic effects in the heart and kidney. However, it is not known whether Ac-SDKP has an anti-inflammatory and antifibrotic effect on conduit arteries such as the aorta. We hypothesize that in ANG II-induced hypertension Ac-SDKP prevents aortic fibrosis and that this effect is associated with decreased protein kinase C (PKC) activation, leading to reduced oxidative stress and inflammation and a decrease in the profibrotic cytokine transforming growth factor-beta1 (TGF-beta1) and phosphorylation of its second messenger Smad2. To test this hypothesis we used rats with ANG II-induced hypertension and treated them with either vehicle or Ac-SDKP. In this hypertensive model we found an increased collagen deposition and collagen type I and III mRNA expression in the aorta. These changes were associated with increased PKC activation, oxidative stress, intercellular adhesion molecule (ICAM)-1 mRNA expression, and macrophage infiltration. TGF-beta1 expression and Smad2 phosphorylation also increased. Ac-SDKP prevented these effects without decreasing blood pressure or aortic hypertrophy. Ac-SDKP also enhanced expression of inhibitory Smad7. These data indicate that in ANG II-induced hypertension Ac-SDKP has an aortic antifibrotic effect. This effect may be due in part to inhibition of PKC activation, which in turn could reduce oxidative stress, ICAM-1 expression, and macrophage infiltration. Part of the effect of Ac-SDKP could also be due to reduced expression of the profibrotic cytokine TGF-beta1 and inhibition of Smad2 phosphorylation.
Lin
Chun-Xia
CX
Hypertension and Vascular Research Div., Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202-2689, USA.
Rhaleb
Nour-Eddine
NE
Yang
Xiao-Ping
XP
Liao
Tang-Dong
TD
D'Ambrosio
Martin A
MA
Carretero
Oscar A
OA
D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications / Q000473:pathology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D014662:Vasoconstrictor Agents
D009842:Oligopeptides; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D004549:Elastin; D011493:Protein Kinase C; C058504:goralatide