Mechanism Of Bortezomib In The Inhibition Of Pulmonary Hypertension By Modulating The Ubiquitin Proteasome System In Rats

BACKGROUND Pulmonary arterial hypertension(PAH) is a common complication of congenital heart disease due to left-to-right shunt, which is an intractable condition characterized by elevated pulmonary arterial pressure leading to right ventricular failure. The essential pathologic feature of high blood flow PAH is the over-proliferation and remodeling of pulmonary arterial endothelial cells (ECs) and smooth muscle cells (SMCs). Majority researches have considered that increased pulmonary blood flow, vascular endothelial cells injury, smooth muscle cells phenotype conversion, over-proliferation, insufficient apoptosis, pulmonary vascular bed reconstruction and lumen obliteration, ultimately lead to PAH. The pathogenesis of PAH involves in kinds of complex cell factors and regulation networks, and their specific pathogenesis is still unclear. Therefore, it’s important to clear the pathogenesis of pulmonary hypertension and seek more effective treatments for PAH.OBJECTIVE To observe the activation of ubiquitin proteasome system and the inhibitive effect of Bortezomib on high-flow pulmonary hypertension in rats model, to explore the mechanism of ubiquitin proteasome system and proliferating cell nuclear antigen(PCNA)/Caspase-3in the inhibition of pulmonary hypertension by Brotezomib.METHODS Forty-five male Wistar rats were randomly divided into a shunt group, a treated group, a control group (n=15each). The rat model of pulmonary hypertension was established by underwent abdominal aorta and inferior vena cava shunt operation, and the control group was given sham operation. After8weeks, to measure the RVSP and RVHI in each group and calculate WT%and WA%after HE staining the left lung. The small pulmonary arterial morphologic changes in each group were studied with microscopy for morphometric analysis. The expression of Ubiquitin, PCNA and Caspase-3were determined by immunohistochemistry and western blot, the activation of nuclear factor kappa B (NF-κB) signal pathway was detected by western blot.RESULTS Compared with the control group, the pulmonary arterial morphologic changes in the operated group showed that the WT%, WA%and RVSP, RVHI (P<0.01) together with the expression of Ub and PCNA (P<0.05) increased significantly, the activity of NF-κB was induced. However, in the treated group, they are deceased significantly than the operated group (P<0.05). The expression of Caspase-3(P<0.05) in the operated group was increased compared with the control group. Compared with the operated group, the expression of Caspase-3(P<0.05) in the treated group was increased, NF-κB activity was inhibited.CONCLUSION The ubiquitin-proteasome system may be induced in the high-flow pulmonary hypertension. Bortezomib may partly prevent the development of pulmonary hypertension by regulating NF-κB pathway to adjust the expression of PCNA/Caspase-3of the pulmonary hypertension rats.