Li Huayang, Liu Quan, Yue Yuan, Wang Shunjun, Huang Suiqing, Huang Lin, Luo Li, Zhang Yitao, Wu Zhongkai
Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.
Cardiovasc Diagn Ther. 2022 Feb;12(1):88-102. doi: 10.21037/cdt-21-360.
Pulmonary arterial hypertension is a progressive angio-proliferative disease associated with high morbidity and mortality rates. Although the histopathology of pulmonary arterial hypertension is well described, its therapeutic option remains unsatisfactory. This study investigated the effect of celastrol treatment on right ventricular dysfunction, remodeling, and pulmonary vascular remodeling in pulmonary arterial hypertension rats as well as its possible mechanisms.
Pulmonary arterial hypertension was induced in male Sprague-Dawley rats by a single subcutaneously injection of monocrotaline. After daily delivery of celastrol (1 mg/kg) or vehicle via intraperitoneal injection for 4 weeks, the effects of celastrol on right ventricular function, fibrosis, and pulmonary vascular remodeling were assessed. The infiltration of macrophages, the expression of inflammatory cytokines, including MCP-1, IL-1β, IL-6, and IL-10, and the expression of NF-κB signaling pathway-associated proteins, IκBα, p-IKKα/β and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells proliferation under hypoxia was studied .
Rats with pulmonary arterial hypertension had decreased right ventricular function, increased right ventricular fibrosis and pulmonary arteries with interstitial thickening and prominent media hypertrophy. Treatment with celastrol improved right ventricular function, attenuated right ventricular fibrosis and pulmonary vascular remodeling. Significantly decreased macrophage infiltration, reduced levels of pro-inflammatory cytokines, increased level of anti-inflammatory cytokine and inhibited NF-κB signaling pathway were observed in the lung tissues of rats treated with celastrol. Moreover, celastrol significantly suppressed the proliferation of human pulmonary artery smooth cells under hypoxia.
We showed that in rats with pulmonary arterial hypertension, celastrol could improve right ventricular function, attenuate right ventricular and pulmonary vascular remodeling, and inhibit human pulmonary artery smooth cells proliferation under hypoxia. Suppression of the nuclear factor-κB (NF-κB) signaling pathway may be a part of the protective mechanism.
肺动脉高压是一种进行性血管增殖性疾病，发病率和死亡率都很高。尽管肺动脉高压的组织病理学已有详细描述，但其治疗选择仍不尽人意。本研究探讨了雷公藤红素治疗对肺动脉高压大鼠右心室功能、重塑及肺血管重塑的影响及其可能机制。
通过单次皮下注射野百合碱诱导雄性Sprague-Dawley大鼠发生肺动脉高压。每天通过腹腔注射给予雷公藤红素（1mg/kg）或溶剂，持续4周，评估雷公藤红素对右心室功能、纤维化及肺血管重塑的影响。进一步检测巨噬细胞浸润情况、包括单核细胞趋化蛋白-1（MCP-1）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和白细胞介素-10（IL-10）在内的炎性细胞因子的表达，以及核因子-κB（NF-κB）信号通路相关蛋白IκBα、磷酸化IκB激酶α/β（p-IKKα/β）和p65的表达。最后，研究雷公藤红素对缺氧条件下人肺动脉平滑肌细胞增殖的影响。
肺动脉高压大鼠右心室功能下降，右心室纤维化增加，肺动脉出现间质增厚和中膜显著肥厚。雷公藤红素治疗可改善右心室功能，减轻右心室纤维化和肺血管重塑。在接受雷公藤红素治疗的大鼠肺组织中，观察到巨噬细胞浸润显著减少、促炎细胞因子水平降低、抗炎细胞因子水平升高以及NF-κB信号通路受到抑制。此外，雷公藤红素在缺氧条件下可显著抑制人肺动脉平滑肌细胞的增殖。
我们发现，在肺动脉高压大鼠中，雷公藤红素可改善右心室功能，减轻右心室和肺血管重塑，并在缺氧条件下抑制人肺动脉平滑肌细胞增殖。抑制核因子-κB（NF-κB）信号通路可能是其保护机制的一部分。
