Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1350-9. doi: 10.1161/ATVBAHA.112.300287. Epub 2013 Apr 4.
Atherosclerosis is an inflammatory disease with multiple underlying metabolic and physical risk factors. Bone morphogenic protein 4 (BMP4) expression is increased in endothelium in atherosclerosis-prone regions and is known to induce endothelial inflammation, endothelial dysfunction, and hypertension. BMP actions are mediated by 2 different types of BMP receptors (BMPRI and BMPRII). Here, we show a surprising finding that loss of BMPRII expression causes endothelial inflammation and atherosclerosis.
Using BMPRII siRNA and BMPRII(+/-) mice, we found that specific knockdown of BMPRII, but not other BMP receptors (Alk1, Alk2, Alk3, Alk6, ActRIIa, and ActRIIb), induced endothelial inflammation in a ligand-independent manner by mechanisms mediated by reactive oxygen species, nuclear factor-KappaB, and reduced nicotinamide adenine dinucleotide phosphate oxidases. Further, BMPRII(+/-)ApoE(-/-) mice developed accelerated atherosclerosis compared with BMPRII(+/+)ApoE(-/-) mice. Interestingly, we found that multiple proatherogenic stimuli, such as hypercholesterolemia, disturbed flow, prohypertensive angiotensin II, and the proinflammatory cytokine (tumor necrosis factor-α), downregulated BMPRII expression in endothelium, whereas antiatherogenic stimuli, such as stable flow and statin treatment, upregulated its expression in vivo and in vitro. Moreover, BMPRII expression was significantly diminished in human coronary advanced atherosclerotic lesions. Also, we were able to rescue the endothelial inflammation induced by BMPRII knockdown by overexpressing the BMPRII wild type, but not by the BMPRII short form lacking the carboxyl-terminal tail region.
These results suggest that BMPRII is a critical, anti-inflammatory, and antiatherogenic protein that is commonly targeted by multiple pro- and antiatherogenic factors. BMPRII may be used as a novel diagnostic and therapeutic target in atherosclerosis.
动脉粥样硬化是一种炎症性疾病，存在多种潜在的代谢和物理危险因素。骨形态发生蛋白 4（BMP4）在易发生动脉粥样硬化的区域内皮细胞中的表达增加，已知其可诱导内皮炎症、内皮功能障碍和高血压。BMP 作用通过 2 种不同类型的 BMP 受体（BMPRI 和 BMPRII）介导。在这里，我们发现了一个令人惊讶的发现，即 BMPRII 表达缺失会导致内皮炎症和动脉粥样硬化。
使用 BMPRII siRNA 和 BMPRII（+/-）小鼠，我们发现，特异性敲低 BMPRII（而不是其他 BMP 受体（Alk1、Alk2、Alk3、Alk6、ActRIIa 和 ActRIIb））以配体非依赖性方式诱导内皮炎症，其机制介导活性氧、核因子-KappaB 和还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶。此外，与 BMPRII（+/+）ApoE（-/-）小鼠相比，BMPRII（+/-）ApoE（-/-）小鼠发生加速动脉粥样硬化。有趣的是，我们发现多种促动脉粥样硬化刺激物，如高胆固醇血症、血流紊乱、促高血压血管紧张素 II 和促炎细胞因子（肿瘤坏死因子-α），下调内皮细胞中的 BMPRII 表达，而抗动脉粥样硬化刺激物，如稳定血流和他汀类药物治疗，在体内和体外均上调其表达。此外，BMPRII 在人冠状动脉晚期动脉粥样硬化病变中的表达明显减少。此外，我们能够通过过表达 BMPRII 野生型来挽救由 BMPRII 敲低引起的内皮炎症，而通过缺乏羧基末端尾部区域的 BMPRII 短型则不能。
这些结果表明，BMPRII 是一种关键的抗炎和抗动脉粥样硬化蛋白，通常是多种促动脉粥样硬化和抗动脉粥样硬化因素的靶点。BMPRII 可作为动脉粥样硬化的一种新型诊断和治疗靶点。
