Loss of Endothelial CXCR7 Impairs Vascular Homeostasis and Cardiac Remodeling After Myocardial Infarction Implications for Cardiovascular Drug Discovery
Loss of Endothelial CXCR7 Impairs Vascular Homeostasis and Cardiac Remodeling After Myocardial Infarction Implications for Cardiovascular Drug Discovery
复制标题
内皮 CXCR7 的缺失会损害心肌梗死后的血管稳态和心脏重塑对心血管药物发现的影响
DOI：
10.1161/circulationaha.116.023027
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发表时间：
2017-03-28
期刊：
影响因子：
37.8
通讯作者：
Wang, Miao
中科院分区：
文献类型：
--
作者：
Hao, Huifeng;Hu, Sheng;Wang, Miao
背景技术背景：全基因组关联研究确定了CXCL12基因位点（编码趋化因子CXCL12，也称为基质细胞衍生因子1）与冠状动脉疾病和心肌梗死（MI）的关联。不像CXCR4，CXCL12的经典受体，CXCR7（最近确定的受体）在血管损伤和MI的反应的功能仍不清楚。携带floxed CXCR7和Cdh5启动子驱动的CreERT2的小鼠用他莫昔芬处理以诱导CXCR7的内皮限制性缺失。研究了所得条件性基因敲除小鼠和同窝对照小鼠对血管成形术导丝损伤的动脉反应和对冠状动脉结扎的心脏反应。CXCR7在内皮细胞增殖和血管生成中的作用用来自小鼠和人的细胞在体外测定。在MI小鼠中评价CXCR7基因的腺病毒递送和CXCR7的药理学激活的效果。结果：人和小鼠的损伤动脉均表现出内皮CXCR7表达。条件性内皮CXCR7缺失促进了内皮损伤后的新生内膜形成而不改变血浆脂质水平，并加剧了MI后的心功能损害，增加了死亡率和梗死面积。从机制上讲，血管和心脏重塑中加剧的反应可归因于CXCR7在促进内皮细胞增殖和血管生成中的关键作用。令人印象深刻的是，受损的MI后心脏重塑发生在CXCL12水平升高的情况下，CXCL12先前被认为通过专门参与其同源受体CXCR4来介导心脏保护。此外，CXCR7基因通过左心室注射和治疗CXCR7激动剂提供心肌保护后MI.CONCLUSIONS：CXCR7代表一种新的调节血管内稳态的功能，在内皮细胞有足够的能力影响心肌梗死后的心脏功能和重塑。CXCR7的激活可能对经皮冠状动脉介入治疗后的临床再狭窄和MI后的心脏重塑具有治疗潜力。
BACKGROUND: Genome-wide association studies identified the association of the CXCL12 genetic 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 floxed CXCR7 and Cdh5-promoter driven CreERT2 were 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 of CXCR7 gene 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, both CXCR7 gene 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.