Prevention of aortic fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in angiotensin II-induced hypertension

• Published in: American journal of physiology. Heart and circulatory physiology 2008-09, Vol.295 (3), p.H1253-H1261
• Main Authors: Lin, Chun-Xia, Rhaleb, Nour-Eddine, Yang, Xiao-Ping, Liao, Tang-Dong, D'Ambrosio, Martin A, Carretero, Oscar A
• Format: Article
• Language: English
• Subjects: ACE inhibitors; Angiotensin II; Animals; Aorta - pathology; Cardiovascular disease; Collagen - biosynthesis; Collagen - genetics; Collagen - metabolism; Disease prevention; Elastin - metabolism; Enzyme Activation - drug effects; Fibrosis; Gene expression; Heart Diseases - etiology; Heart Diseases - pathology; Heart Diseases - prevention & control; Hypertension; Hypertension - chemically induced; Hypertension - complications; Hypertension - pathology; Immunohistochemistry; Intercellular Adhesion Molecule-1 - biosynthesis; Kinases; Lipid Metabolism - drug effects; Male; Neutrophil Infiltration - drug effects; Oligopeptides - pharmacology; Oxidation-Reduction; Phosphorylation; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Smad2 Protein - metabolism; Transforming Growth Factor beta1 - biosynthesis; Transforming Growth Factor beta1 - genetics; Vasoconstrictor Agents
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00481.2008

Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan Submitted 8 May 2008 ; accepted in final form 14 July 2008 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-β1 (TGF-β1) 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-β1 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-β1 and inhibition of Smad2 phosphorylation. arteriosclerosis; vascular hypertrophy; inflammation; protein kinase C; transforming growth factor-β1/Smad Address for reprint requests and other correspondence: O. A. Carretero, Hypertension and Vascular Research Div., Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202-2689 (e-mail: ocarret1{at}hfhs.org )