Congcong Zhang1, Yulin Li1, Chunxiao Wang1, Yina Wu1, Wei Cui1, Takashi Miwa1, Sayaka Sato1, Huihua Li1, Wen-Chao Song2, Jie Du2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Ulrich Wenzel; Jan Eric Turner; Christian Krebs; Christian Kurts; David G Harrison; Heimo Ehmke Journal: J Am Soc Nephrol Date: 2015-08-28 Impact factor: 10.121
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312