title: 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.
authors.affiliation: *Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, U.S.A.
authors.forename: Germán E
authors.initials: GE
authors.lastname: González
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Pablo
authors.initials: P
authors.lastname: Nakagawa
authors.forename: Tang-Dong
authors.initials: TD
authors.lastname: Liao
authors.forename: Yunhe
authors.initials: Y
authors.lastname: Liu
authors.forename: Pablo
authors.initials: P
authors.lastname: Leung
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Dai
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006332:Cardiomegaly / Q000139:chemically induced; D003094:Collagen / Q000187:drug effects* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use* / Q000652:urine; D009929:Organ Size / Q000187:drug effects; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D009842:Oligopeptides; D012333:RNA, Messenger; D000804:Angiotensin II; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C574516:LOXL1 protein, rat; D008249:Protein-Lysine 6-Oxidase; C058504:goralatide