Loss of Endothelial CXCR7 Impairs Vascular Homeostasis and Cardiac Remodeling After Myocardial Infarction: Implications for Cardiovascular Drug Discovery.
BACKGROUND
Genome-wide association studies identified the association of theCXCL12genetic locus (which encodes the chemokine CXCL12, also known as stromal cell-derived factor 1) with coronary artery disease and myocardial infarction (MI). Unlike CXCR4, the classic receptor for CXCL12, the function of CXCR7 (the most recently identified receptor) in vascular responses to injury and in MI remains unclear.


METHODS
Tissue expression of CXCR7 was examined in arteries from mice and humans. Mice that harbored floxedCXCR7andCdh5-promoter drivenCreERT2were treated with tamoxifen to induce endothelium-restricted deletion of CXCR7. The resulting conditional knockout mice and littermate controls were studied for arterial response to angioplasty wire injury and cardiac response to coronary artery ligation. The role of CXCR7 in endothelial cell proliferation and angiogenesis was determined in vitro with cells from mice and humans. The effects of adenoviral delivery ofCXCR7gene and pharmacological activation of CXCR7 were evaluated in mice subjected to MI.


RESULTS
Injured arteries from both humans and mice exhibited endothelial CXCR7 expression. Conditional endothelial CXCR7 deletion promoted neointimal formation without altering plasma lipid levels after endothelial injury and exacerbated heart functional impairment after MI, with increased both mortality and infarct sizes. Mechanistically, the exacerbated responses in vascular and cardiac remodeling are attributable to the key role of CXCR7 in promoting endothelial proliferation and angiogenesis. Impressively, the impaired post-MI cardiac remodeling occurred with elevated levels of CXCL12, which was previously thought to mediate cardiac protection by exclusively engaging its cognate receptor, CXCR4. In addition, bothCXCR7gene delivery via left ventricular injection and treatment with a CXCR7 agonist offered cardiac protection after MI.


CONCLUSIONS
CXCR7 represents a novel regulator of vascular homeostasis that functions in the endothelial compartment with sufficient capacity to affect cardiac function and remodeling after MI. Activation of CXCR7 may have therapeutic potential for clinical restenosis after percutaneous coronary intervention and for heart remodeling after MI.
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Huifeng
H
Hao
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Sheng
S
Hu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Hong
H
Chen
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Dawei
D
Bu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Liyuan
L
Zhu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Chuansheng
C
Xu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Fei
F
Chu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Xingyu
X
Huo
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Yue
Y
Tang
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Xiaogang
X
Sun
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Bi-Sen
BS
Ding
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
De-Pei
DP
Liu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.).
Shengshou
S
Hu
From State Key Laboratory of Cardiovascular Disease (H.H., Sheng Hu, D.B., L.Z., C.X., F.C., X.H., Shengshou Hu, M.W.), Animal Experimental Center (Y.T.), Department of Cardiovascular Surgery (X.S., Shengshou Hu), and Clinical Pharmacology Center (M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pharmacology, Shihezi University, Shihezi, Xinjiang, China (C.X.); Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China (F.C.); Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY (B.D.); and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.L.). wangmiao_frank@yahoo.com miao.wang@pumc.edu.cn.
Miao
M
Wang
D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery; D055106:Genome-Wide Association Study / Q000379:methods*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy; D054387:Receptors, CXCR; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000187:drug effects*
C501896:ACKR3 protein, human; D054387:Receptors, CXCR
cardiovascular diseases; endothelial cells; heart failure; myocardial infarction; vascular remodeling