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.
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Authors | Germán E González, Nour-Eddine Rhaleb, Pablo Nakagawa, Tang-Dong Liao, Yunhe Liu, Pablo Leung, Xiangguo Dai, Xiao-Ping Yang, Oscar A Carretero |
Journal | Clinical science (London, England : 1979)
(Clin Sci (Lond))
Vol. 126
Issue 1
Pg. 85-94
(Jan 01 2014)
ISSN: 1470-8736 [Electronic] England |
PMID | 23834332
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- NF-kappa B
- Oligopeptides
- RNA, Messenger
- Angiotensin II
- Collagen
- Amino Acid Oxidoreductases
- LOXL1 protein, rat
- Protein-Lysine 6-Oxidase
- goralatide
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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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