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−1·d−1 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.
*School of Biomedical Sciences; and
†Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
‡Department of Biological and Physical Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia.
Reprints: Lindsay Brown, PhD, Department of Biological and Physical Sciences, University of Southern Queensland, Toowoomba, Queensland 4350, Australia (e-mail: email@example.com).
Supported in part by the National Health and Medical Research Council of Australia and Dr Red Nutraceuticals, Mt Nebo, Queensland, Australia; the ANZ Trustees Medical Research in Queensland Program (A.I.); the Australian Research Council for a Federation Fellowship (to D.P.F.).
D. P. Fairlie was the Scientific Director, CSO, and one of the founders of Promics Pty, Ltd, at the time these studies were initiated.
D. P. Fairlie, S. M. Taylor, and L. Brown are inventors on several patents associated with PMX53 and filed by The University of Queensland.
The authors report no conflicts of interest.
Received April 18, 2011
Accepted June 21, 2011