Abstract
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.
Highlights
Pulmonary arterial hypertension (PAH) is a life-threatening disorder, characterized by vascular remodeling of small pulmonary arteries, which leads to sustained elevation of mean pulmonary artery pressure, right ventricular (RV) afterload and hypertrophy, and eventually RV failure [1,2,3]
Because AKT activation has been increasingly recognized as a regulator of vascular remodeling and controversy persists regarding the role of AKT in HIF-1α regulation, we explored a possible link between AKT phosphorylation and HIF-1α expression in hypoxia- and platelet-derived growth factor (PDGF)-BB-induced human pulmonary artery smooth muscle cells (hPASMCs) and assessed the effects of caffeic acid phenethyl ester (CAPE) on HIF-1α expression
These results suggested that administration of CAPE attenuates hypoxiaand PDGF-BB-induced HIF-1α expression and that it is mediated through AKT/ERK inactivation in hPASMCs
Summary
Pulmonary arterial hypertension (PAH) is a life-threatening disorder, characterized by vascular remodeling of small pulmonary arteries, which leads to sustained elevation of mean pulmonary artery pressure, right ventricular (RV) afterload and hypertrophy, and eventually RV failure [1,2,3]. Aberrant proliferation and resistance of pulmonary arterial smooth muscle cells (PASMCs) to apoptosis in the tunica media of the pulmonary artery are promoted by various growth factors, and these phenomena are the major cause of vascular remodeling in the development of PAH [4]. It has been recognized that hypoxia plays a vital role in the development of PAH, molecular and cellular mechanisms driving vascular remodeling remain poorly defined. Hypoxia-induced smooth muscle cells proliferation is inhibited by HIF-1α knock-down [10], suggesting that HIF-1 may participate in pulmonary vascular remodeling. Considerable efforts have been made to understand the cellular mechanisms of HIF-1α-associated pulmonary vascular remodeling and PASMC proliferation and migration, the relationship between HIF-1α and PDGF-BB in the MCT-induced rat PAH model remains controversial
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