Sclerostin ablation prevents aortic valve stenosis in mice.
Sclerostin ablation prevents aortic valve stenosis in mice.
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硬化蛋白消融可预防小鼠主动脉瓣狭窄。
DOI：
10.1152/ajpheart.00355.2022
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Merryman,WDavid
中科院分区：
文献类型：
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作者：
Joll2nd,JEthan;Riley,LanceA;Bersi,MatthewR;Nyman,JeffryS;Merryman,WDavid
本研究的目的是检验靶向硬化素会加速主动脉瓣狭窄进展的假设。 Sclerostin（小鼠基因，Sost）是一种分泌性糖蛋白，可作为骨重塑的有效调节剂。针对硬化蛋白的抗体疗法被批准用于治疗骨质疏松症，但 III 期临床试验的结果显示多种脱靶心血管效应。生成野生型（WT，Sost+/+）和Sost基因敲除表达（Null，Sost−/−）小鼠，并通过高胆固醇饮食维持至12月龄，以诱导主动脉瓣狭窄。通过超声心动图、组织学和 RNAseq 对小鼠进行检查。从每种基因型开发永生化瓣膜间质细胞用于体外研究。无效小鼠出现骨过度生长表型，与硬化症患者类似。然而，令人惊讶的是，WT 小鼠出现了主动脉瓣狭窄的血流动力学迹象，而 Null 小鼠则没有变化。 WT 小鼠的主动脉瓣叶较厚，α-平滑肌肌动蛋白含量较高，α-平滑肌肌动蛋白是肌成纤维细胞活化和营养不良性钙化的标志物，但几乎没有 Runx2 表达的证据，而 Runx2 是成骨钙化的标志物。主动脉根部的 RNAseq 分析表明转录因子 HOX 家族在 Null 小鼠中显着上调，并且来自 Null 动物的瓣膜间质细胞富含 Hoxa1、Hoxb2 和 Hoxd3 亚型，而 Hoxa7 下调。此外，零瓣膜间质细胞的收缩性低于 WT 细胞。与我们的假设相反，硬化素靶向预防了主动脉瓣狭窄的症状，并表明针对骨质疏松症的靶向抗体治疗可能对这些主动脉瓣狭窄患者有益。新的和值得注意的我们发现，Sostgene（蛋白质：硬化素）的基因消除可以预防老年西方饮食小鼠的主动脉瓣狭窄。这是硬化蛋白在心血管系统中的新作用。据作者所知，这是第一个在心血管疾病模型中直接操纵硬化蛋白的研究之一，也是第一个专门研究主动脉瓣的研究。我们还指出了 Hoxgenes 在心血管疾病中的潜在新作用，注意到硬化蛋白基因敲除的主动脉根部的泛 Hox 上调。 Hoxgenes 在产后心血管健康和疾病中的作用是本文贡献的另一个新兴研究领域。
The objective of this study was to test the hypothesis that targeting sclerostin would accelerate the progression of aortic valve stenosis. Sclerostin (mouse gene,Sost) is a secreted glycoprotein that acts as a potent regulator of bone remodeling. Antibody therapy targeting sclerostin is approved for osteoporosis but results from astage IIIclinical trial showed multiple off-target cardiovascular effects. Wild-type (WT,Sost+/+) andSost-gene knockout-expression (Null,Sost−/−) mice were generated and maintained to 12 mo of age on a high-cholesterol diet to induce aortic valve stenosis. Mice were examined by echocardiography, histology, and RNAseq. Immortalized valve interstitial cells were developed from each genotype for in vitro studies. Null mice developed a bone overgrowth phenotype, similar to patients with sclerosteosis. Surprisingly, however, WT mice developed hemodynamic signs of aortic valve stenosis, whereas Null mice were unchanged. WT mice had thicker aortic valve leaflets and higher amounts of α-smooth muscle actin, a marker myofibroblast activation and dystrophic calcification, with very little evidence of Runx2 expression, a marker of osteogenic calcification. RNAseq analysis of aortic roots indicated the HOX family of transcription factors was significantly upregulated in Null mice, and valve interstitial cells from Null animals were enriched with Hoxa1, Hoxb2, and Hoxd3 subtypes with downregulated Hoxa7. In addition, Null valve interstitial cells were shown to be less contractile than their WT counterparts. Contrary to our hypothesis, sclerostin targeting prevented hallmarks of aortic valve stenosis and indicates that targeted antibody treatments for osteoporosis may be beneficial for these patients regarding aortic stenosis.NEW & NOTEWORTHYWe have found that genetic ablation of theSostgene (protein: sclerostin) prevents aortic valve stenosis in aged, Western diet mice. This is a new role for sclerostin in the cardiovascular system. To the knowledge of the authors, this is one of the first studies directly manipulating sclerostin in a cardiovascular disease model and the first to specifically study the aortic valve. We also provide a potential new role forHoxgenes in cardiovascular disease, noting pan-Hoxupregulation in the aortic roots of sclerostin genetic knockouts. The role ofHoxgenes in postnatal cardiovascular health and disease is another burgeoning field of study to which this article contributes.