Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Arterioscler Thromb Vasc Biol. 2021 Mar;41(3):1205-1217. doi: 10.1161/ATVBAHA.120.315731. Epub 2021 Jan 21.
Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.
These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.
肺动脉高压的特征是肺动脉平滑肌细胞异常增殖和血管重构，导致右心室（RV）衰竭。Bsg（Basigin）是一种跨膜糖蛋白，可促进成肌纤维细胞分化、细胞增殖和基质金属蛋白酶激活。CyPA（亲环素 A）与它的受体 Bsg 结合，促进肺动脉平滑肌细胞增殖和炎症细胞募集。我们之前报道过，Bsg 在小鼠的压力超负荷左心室中促进心肌纤维化和衰竭。然而，Bsg 和 CyPA 在 RV 衰竭中的作用仍有待阐明。方法和结果：首先，我们发现缺氧诱导的肺动脉高压（PH）小鼠和野百合碱诱导的 PH 大鼠心脏中 Bsg 和 CyPA 的蛋白水平上调。此外，与同窝仔相比，心肌细胞特异性过表达 Bsg 的小鼠在慢性缺氧和肺动脉结扎后表现出更严重的 RV 肥大、纤维化和功能障碍。通过药物筛选，我们发现 celastrol 是 Bsg 和 CyPA 的抑制剂，celastrol 可降低肺动脉平滑肌细胞的增殖、活性氧和炎症细胞因子。此外，celastrol 可改善缺氧诱导的 PH 小鼠的 RV 收缩压、肥大、纤维化和功能障碍，以及 SU5416/缺氧诱导的 PH 大鼠的 RV 功能障碍，同时降低心脏和肺部的 Bsg、CyPA 和炎症细胞因子。结论：这些结果表明，压力超负荷 RV 中的 Bsg 升高可加重 RV 功能障碍，而 celastrol 通过抑制 Bsg 及其配体 CyPA 可改善 PH 模型动物的 RV 功能障碍。因此，celastrol 可作为一种针对 Bsg 和 CyPA 的新型 PH 和 RV 衰竭药物。
