title: Complement 5a receptor mediates angiotensin II-induced cardiac inflammation and remodeling.
abstract: OBJECTIVE
  Inflammation contributes to hypertension-induced cardiac damage and fibrotic remodeling. Complement activation produces anaphylatoxins, which are major inflammatory effectors. Here, we investigated the role of complement anaphylatoxins in angiotensin II (Ang II)-induced cardiac remodeling.
  
  
  RESULTS
  We measured human plasma levels of complement anaphylatoxins in hypertensive individuals and controls and studied the role of complement activation in a mouse model of Ang II-induced hypertension and cardiac injury. We found that complement 5a (C5a) concentration was more elevated in hypertensive individuals than in controls. Infusion of Ang II in mice for 7 days led to increased anaphylatoxin concentration in plasma and perivascular C3b deposition in the heart. C5a receptor (C5aR)-deficient but not C3a receptor-deficient mice exhibited markedly reduced cardiac remodeling and inflammation after Ang II infusion. Pharmacological inhibition of C5a production by an anti-C5 monoclonal antibody produced similar effects to C5aR deficiency. Bone marrow chimera experiments revealed that C5aR expression on bone marrow-derived cells was critical in mediating Ang II-induced cardiac injury and remodeling. The C5aR pathway regulated the expression of adhesion molecules on peripheral monocytes, as well as infiltration and cytokine production of macrophage in the heart.
  
  
  CONCLUSIONS
  Complement is activated in hypertensive hearts, and the C5aR signaling pathway on blood monocytes/macrophages plays a pathological role in Ang II-induced cardiac inflammation and remodeling. Therapeutic inhibition of complement may protect patients from hypertension-related heart injury.
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Yina
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sato
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.).
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.). songwe@upenn.edu jdu@bcm.edu.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
authors.affiliation: From the Department of Vascular Biology, Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China (C.Z., Y.L., C.W., Y.W., W.C., H.L., J.D.); and Department of Pharmacology and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.M., S.S., W.-C.S.). songwe@upenn.edu jdu@bcm.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003167:Complement Activation; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000276:immunology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000209:etiology*; D044087:Receptor, Anaphylatoxin C5a / Q000502:physiology*; D011951:Receptors, Complement / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D000804:Angiotensin II
keywords: angiotensin II; complement C5a; complement system proteins; hypertension; inflammation