Celastrol attenuates the remodeling of pulmonary vascular and right ventricular in monocrotaline-induced pulmonary arterial hypertension in rats

Background: 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. Methods: 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-1 beta, IL-6, and IL-10, and the expression of NF-Kappa B signaling pathway-associated proteins, I Kappa B alpha, p-IKK alpha/beta and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells proliferation under hypoxia was studied in vitro. Results: 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-Kappa B 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. Conclusions: 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-Kappa B (NF-Kappa B) signaling pathway may be a part of the protective mechanism.