Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction.
BACKGROUND
The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown.


METHODS
Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+cells in normotensive controls and hypertension patients were analyzed by flow cytometry.


RESULTS
Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+CXCR2+cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/-bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20).


CONCLUSIONS
Infiltration of CXCR2+cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Lei
L
Wang
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Xue-Chen
XC
Zhao
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Wei
W
Cui
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Yong-Qiang
YQ
Ma
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Hua-Liang
HL
Ren
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Xin
X
Zhou
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
John
J
Fassett
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Yan-Zong
YZ
Yang
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Yingjie
Y
Chen
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Yun-Long
YL
Xia
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.).
Jie
J
Du
From Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China (L.W., X.-C.Z., Y.Z.Z., Y.-L.X., H.-H.L.); Beijing Anzhen Hospital, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing, China (W.C., J.D.); Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital Heart Center, Tianjin, China (Y.-Q.M., X.Z.); Department of Vascular Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (H.-L.R.); Department of Pharmacology and Toxicology, University of Graz, Graz, Austria (J.F.); Cardiovascular Division, University of Minnesota, Minneapolis, MN (Y.C.); and Department of Nutrition and Food Hygiene, School of Public Health, Advanced Institute of Medical Sciences, Dalian Medical University, Dalian, China (H.-H.L.). hhli1935@aliyun.com yunlong_xia@126.com.
Hui-Hua
HH
Li
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D066253:Vascular Remodeling / Q000187:drug effects* / Q000235:genetics
D023063:Receptors, Interleukin-8B; D000804:Angiotensin II
CXCR2; chemoreceptor; hypertension; inflammation; oxidant stress
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