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

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 Angll (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 TGF beta (transforming growth factor beta) and the pro-inflammatory transcription factor NF-kappa B (nuclear factor kappa B) and CD4(+)/CD8(+) lymphocyte infiltration. We induced hypertension in rats by infusing Angll 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 Angll-induced increases in (i) cross-linked and total collagen, (ii) LOX mRNA expression and LOXL1 (LOX-like 1) protein, (iii) TGF beta expression, (iv) nuclear translocation of NF-kappa B, (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 TGF beta 1, LOXL1, and lymphocyte and macrophage infiltration, and its effect on inflammation could be due to lower NF-kappa B.