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.
N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats
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Germán E. González, Nour-Eddine Rhaleb, Pablo Nakagawa, Tang-Dong Liao, Yunhe Liu, Pablo Leung, Xiangguo Dai, Xiao-Ping Yang, Oscar A. Carretero; N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats. Clin Sci (Lond) 1 January 2014; 126 (1): 85–94. doi: https://doi.org/10.1042/CS20120619
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