Retinol-binding protein 7 is an endothelium-specific PPARγ cofactor mediating an antioxidant response through adiponectin
Retinol-binding protein 7 is an endothelium-specific PPARγ cofactor mediating an antioxidant response through adiponectin
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DOI：
10.1172/jci.insight.91738
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发表时间：
2017-03-01
期刊：
影响因子：
8
通讯作者：
Sigmund, Curt D.
中科院分区：
文献类型：
--
作者：
Hu, Chunyan;Keen, Henry L.;Sigmund, Curt D.
PPAR受损。内皮细胞的活性导致氧化应激和内皮功能障碍，从而导致高血压易感性，但保护内皮的关键PPAR γ靶基因的身份仍不清楚。视黄醇结合蛋白7 （RBP7）是一种PPAR γ靶基因，本质上是内皮特异性的。虽然rbp7缺陷小鼠在基线时内皮功能正常，但它们在心血管应激源（包括高脂肪饮食和亚压血管紧张素II）下表现出严重的内皮功能障碍。内皮功能障碍不是由于体重增加、葡萄糖稳态受损或肝纤维化的差异，而是通过氧化应激依赖机制发生的，该机制可以通过超氧化物清道夫来拯救。RNA测序显示RBP7需要介导罗格列酮在内皮细胞中诱导PPAR γ靶基因亚群，包括脂联素。高脂饮食和罗格列酮可选择性诱导脂联素在对照组小鼠的内皮细胞中产生，而RBP7缺乏则可消除这种诱导作用。脂联素抑制引起对照血管内皮功能障碍，而脂联素治疗rbp7缺陷血管可改善内皮依赖性松弛并减少氧化应激。我们得出结论，RBP7需要通过脂联素介导PPAR γ在内皮中的保护作用，RBP7是内皮特异性PPAR γ靶点和PPAR γ活性调节剂。
Impaired PPAR. activity in endothelial cells causes oxidative stress and endothelial dysfunction which causes a predisposition to hypertension, but the identity of key PPAR gamma target genes that protect the endothelium remain unclear. Retinol-binding protein 7 (RBP7) is a PPAR gamma target gene that is essentially endothelium specific. Whereas RBP7-deficient mice exhibit normal endothelial function at baseline, they exhibit severe endothelial dysfunction in response to cardiovascular stressors, including high-fat diet and subpressor angiotensin II. Endothelial dysfunction was not due to differences in weight gain, impaired glucose homeostasis, or hepatosteatosis, but occurred through an oxidative stress-dependent mechanism which can be rescued by scavengers of superoxide. RNA sequencing revealed that RBP7 was required to mediate induction of a subset of PPAR gamma target genes by rosiglitazone in the endothelium including adiponectin. Adiponectin was selectively induced in the endothelium of control mice by high-fat diet and rosiglitazone, whereas RBP7 deficiency abolished this induction. Adiponectin inhibition caused endothelial dysfunction in control vessels, whereas adiponectin treatment of RBP7-deficient vessels improved endothelium-dependent relaxation and reduced oxidative stress. We conclude that RBP7 is required to mediate the protective effects of PPAR gamma in the endothelium through adiponectin, and RBP7 is an endothelium-specific PPAR gamma target and regulator of PPAR gamma activity.