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N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats.

Abstract
We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis and inflammation (in macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and ECM (extracellular matrix) formation in hypertension. Thus we hypothesized that (i) in AngII (angiotensin II)-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating LOX (lysyl oxidase), the enzyme responsible for cross-linking, and (ii) these effects are associated with decreased pro-fibrotic cytokine TGFβ (transforming growth factor β) and the pro-inflammatory transcription factor NF-κB (nuclear factor κB) and CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing AngII either alone or combined with Ac-SDKP for 3 weeks. Whereas Ac-SDKP failed to lower BP (blood pressure) or LV (left ventricular) hypertrophy, it did prevent AngII-induced increases in (i) cross-linked and total collagen, (ii) LOX mRNA expression and LOXL1 (LOX-like 1) protein, (iii) TGFβ expression, (iv) nuclear translocation of NF-κB, (v) CD4+/CD8+ lymphocyte infiltration, and (vi) CD68+ macrophages infiltration. In addition, we found a positive correlation between CD4+ infiltration and LOXL1 expression. In conclusion, the effect of Ac-SDKP on collagen cross-linking and total collagen may be due to reduced TGFβ1, LOXL1, and lymphocyte and macrophage infiltration, and its effect on inflammation could be due to lower NF-κB.
AuthorsGermán E González, Nour-Eddine Rhaleb, Pablo Nakagawa, Tang-Dong Liao, Yunhe Liu, Pablo Leung, Xiangguo Dai, Xiao-Ping Yang, Oscar A Carretero
JournalClinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 126 Issue 1 Pg. 85-94 (Jan 01 2014) ISSN: 1470-8736 [Electronic] England
PMID23834332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • NF-kappa B
  • Oligopeptides
  • RNA, Messenger
  • Angiotensin II
  • Collagen
  • Amino Acid Oxidoreductases
  • LOXL1 protein, rat
  • Protein-Lysine 6-Oxidase
  • goralatide
Topics
  • Amino Acid Oxidoreductases (metabolism)
  • Angiotensin II
  • Animals
  • Body Weight (drug effects)
  • CD4-Positive T-Lymphocytes (immunology)
  • Cardiomegaly (chemically induced)
  • Collagen (drug effects, metabolism)
  • Extracellular Matrix (metabolism)
  • Hypertension (chemically induced, complications, immunology)
  • Inflammation (drug therapy, etiology, immunology, metabolism)
  • Lung (pathology)
  • Male
  • NF-kappa B (metabolism)
  • Oligopeptides (pharmacology, therapeutic use, urine)
  • Organ Size (drug effects)
  • Protein-Lysine 6-Oxidase (biosynthesis, genetics)
  • RNA, Messenger (genetics)
  • Rats
  • Rats, Inbred Lew
  • Reverse Transcriptase Polymerase Chain Reaction (methods)
  • Ventricular Function, Left (drug effects)
  • Ventricular Remodeling (drug effects)

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