Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry (J.G., S.T.), James Cook University, Townsville, Queensland, Australia.
The Australian Institute of Tropical Health and Medicine J.G.' S.T.), James Cook University, Townsville, Queensland, Australia.
Arterioscler Thromb Vasc Biol. 2022 Jul;42(7):e187-e202. doi: 10.1161/ATVBAHA.122.317635. Epub 2022 May 12.
Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin's role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83-1.57]; =0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53-1.59]; =0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.
骨硬化蛋白最被人认可的作用是控制骨形成，但它也在心脏、主动脉、冠状动脉和外周动脉中表达。这篇综述总结了骨硬化蛋白在心血管疾病中的作用的研究。啮齿动物研究发现骨硬化蛋白在动脉钙化部位表达。相比之下，有研究报道在腹主动脉瘤的小鼠模型中，主动脉骨硬化蛋白表达下调，而转基因上调或骨硬化蛋白给药被发现可预防腹主动脉瘤和动脉粥样硬化形成。有研究报道骨硬化蛋白缺乏可刺激一种啮齿动物模型的心脏破裂。在人类中，11 项研究中有 7 项报道血清骨硬化蛋白水平高与颈动脉内膜中层厚度高之间存在显著关联。15 项研究中有 10 项报道血清骨硬化蛋白水平高与严重动脉钙化之间存在显著关联。14 项研究中有 12 项报道血清骨硬化蛋白水平高与动脉僵硬度或动脉粥样硬化严重程度之间存在显著关联。9 项研究中有 4 项报道血清骨硬化蛋白水平高与心血管事件风险增加之间存在显著关联。一项随机对照试验的荟萃分析表明，骨硬化蛋白阻断抗体罗莫佐单抗给药并未显著增加主要不良心血管事件的风险（风险比，1.14 [95%CI，0.83-1.57]；=0.54）或心血管死亡（风险比，0.92 [95%CI，0.53-1.59]；=0.71）。人类遗传研究报道，易发生低动脉骨硬化蛋白表达的变异与心血管事件风险增加相关。总体而言，过去的研究表明骨硬化蛋白具有心血管保护作用，但研究结果不一致，这可能是由于研究设计、研究人群和模型的独特性以及所使用的方法的异质性所致。
