title: Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats.
abstract: The anaphylatoxin C5a generated by activation of the innate immunity complement system is a potent inflammatory peptide mediator through the G-protein-coupled receptor C5aR (CD88) present in immune-inflammatory cells, including monocytes, macrophages, neutrophils, T cells, and mast cells. Inflammatory cells infiltrate and initiate the development of fibrosis in the chronically hypertensive heart. In this study, we have investigated whether treatment with a selective C5aR antagonist prevents cardiovascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Control and DOCA-salt rats were treated with PMX53 (AcF-[OPdChaWR], 1 mg·kg·d oral gavage) for 32 days; structural and functional changes in cardiovascular system were determined. DOCA-salt hypertension increased leukocyte extravasation into ventricular tissue, increasing collagen deposition and ventricular stiffness; PMX53 treatment attenuated these changes, thereby improving cardiac function. Further, treatment with PMX53 suppressed an increased expression of C5aR in the left ventricle from DOCA-salt rats, consistent with the reduced infiltration of inflammatory cells. Vascular endothelial dysfunction in thoracic aortic rings was attenuated by PMX53 treatment, but systolic blood pressure was unchanged in DOCA-salt rats. In the heart, PMX53 treatment attenuated inflammatory cell infiltration, fibrosis, and ventricular stiffness, indicating that C5aR is critically involved in ventricular remodeling by regulating inflammatory responses in the hypertensive heart.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Abishek
authors.initials: A
authors.lastname: Iyer
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.forename: Mike C L
authors.initials: MC
authors.lastname: Wu
authors.forename: Con
authors.initials: C
authors.lastname: Stylianou
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003900:Desoxycorticosterone / Q000494:pharmacology*; D004452:Echocardiography; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D018754:Ventricular Dysfunction / Q000503:physiopathology / Q000517:prevention & control
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D009599:Nitroprusside; D003900:Desoxycorticosterone; D003094:Collagen; D000109:Acetylcholine; D009638:Norepinephrine