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

Abstract

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.

• Authors: Chun-Xia Lin, Nour-Eddine Rhaleb, Xiao-Ping Yang, Tang-Dong Liao, Martin A D'Ambrosio, Oscar A Carretero
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 295 Issue 3 Pg. H1253-H1261 (Sep 2008) ISSN: 0363-6135 [Print] United States
• PMID: 18641275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Oligopeptides
• Smad2 Protein
• Transforming Growth Factor beta1
• Vasoconstrictor Agents
• Angiotensin II
• Intercellular Adhesion Molecule-1
• Collagen
• Elastin
• Protein Kinase C
• goralatide

Topics

• Angiotensin II
• Animals
• Aorta (pathology)
• Collagen (biosynthesis, genetics, metabolism)
• Elastin (metabolism)
• Enzyme Activation (drug effects)
• Fibrosis
• Heart Diseases (etiology, pathology, prevention & control)
• Hypertension (chemically induced, complications, pathology)
• Immunohistochemistry
• Intercellular Adhesion Molecule-1 (biosynthesis)
• 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, genetics)
• Vasoconstrictor Agents