lignans and Hypertension--Pulmonary

Topics: Animals; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Hypertension, Pulmonary; Hypoxia; Lignans; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vascular Remodeling

Abnormal autophagy plays critical roles in the structure and function of the pulmonary vasculature. Cyclophilin A (CyPA) can be secreted from cells in response to hypoxia and oxidative stress, which are involved in inducing autophagy and regulating the function of endothelial cells in pulmonary arterial hypertension. Honokiol is a small molecule natural compound; it has many bioactivities, such as antitumor, anti-inflammatory, antioxidant and antiangiogenic properties, but how honokiol mediates autophagy in pulmonary arterial hypertension is unclear. Rat' lungs gavaged with honokiol were examined for autophagy via western blot and fluorescence microscopy. In addition, western blot, quantitative RT-PCR and immunofluorescence were employed to test the expression of CyPA and autophagy markers in pulmonary artery endothelial cells (PAECs). Small interfering RNA targeting CyPA (si-CyPA) was used to knockdown the expression of CyPA, and then autophagy was tested with mRFP-GFP-LC3 fluorescence microscopy and western blot. We found that honokiol could reduce the expression of CyPA and autophagy markers in vivo and in vitro. Furthermore, autophagy was also down-regulated by si-CyPA. Taken together, we revealed a novel mechanism by which honokiol regulates autophagy. The results revealed that honokiol can alleviate autophagy and pulmonary arterial hypertension regulated by CyPA in PAECs.

Topics: Animals; Autophagy; Biphenyl Compounds; Blotting, Western; Cattle; Cells, Cultured; Cyclophilin A; Endothelial Cells; Endothelium, Vascular; Hypertension, Pulmonary; Lignans; Male; Microscopy, Fluorescence; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Pulmonary arterial smooth muscle cells (PASMCs) in the medial layer of the vessel wall are involved in vessel homeostasis, but also for pathologic vascular remodeling in diverse diseases, such as pulmonary arterial hypertension (PAH). Pulmonary vascular remodeling in PAH results in vascular disorders, but its underlying molecular mechanisms are still not to be fully disclosed. In this study, we investigated the expression and function of the transforming growth factor (TGF)-β1 in human PASMC cultured under the condition of hypoxia and elucidated the effect of schisandra chinensis and its active ingredients on proliferation, migration, and apoptosis in human PASMCs. We demonstrated that schisandrin B (Sch.B) alleviated the severity of PAH in PASMCs cultured under the condition of hypoxia. Significant upregulation of TGF-β1 was observed in hypoxia-induced human PASMCs. Interestingly, administration of Sch.B substantially attenuated TGF-β1 level in these PASMCs. In order to elucidate Sch.B function, the hypoxia-induced human PASMC was stimulated with Sch.B or cotreatment with TGF-β1 in vitro. In agreement with its TGF-β1-reducing effect, Sch B relieved human PASMCs migration and promoted the apoptosis of human PASMCs, by activation of TGF-β1 downstream signal pathways in PASMCs. In contrast, co-treatment with TGF-β1 promoted human PASMC proliferation and migration and inhibited the apoptosis of human PASMC, which can attenuate the protective role of Sch.B in human PASMC. Taken collectively, these findings suggest that the vascular relaxation evoked by Sch.B was mediated by direct effect on vascular smooth muscle cell via TGF-β1 downstream signal pathways.

Topics: Antineoplastic Agents; Apoptosis; Cell Movement; Cells, Cultured; Cyclooctanes; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Humans; Hypertension, Pulmonary; Hypoxia; Immunochemistry; Lignans; Medicine, Chinese Traditional; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polycyclic Compounds; Pulmonary Artery; Schisandra; Signal Transduction; Transforming Growth Factor beta1; Up-Regulation; Vascular Remodeling

To observe the effect of sesamin (Ses) on pulmonary vascular remodeling in rats with monocrotaline ( MCT)-induced pulmonary hypertension (PH).. Totally 48 male Sprague-Dawley (SD) rats were fed adaptively for one week and then divided into the normal control group, the MCT group, the MCT +Ses (50 mg x kg(-1)) group and the MCT + Ses (100 mg x kg(-1)) group, with 12 rats in each group. The PH rat model was induced through the subcutaneous injection with MCT(60 mg x kg(-1)). After the administration for four weeks, efforts were made to measure the right ventricular systolic pressure( RVSP) and mean pulmonary artery pressure (mPAP) through right jugular vein catheterization, and isolate right ventricle( RV) and left ventricle( LV) +septum (S) and measure their length to calculate RV/ ( LV + S) and ratio of RV to tibial length. Pathologic changes in arterioles were observed by HE staining. Masson's trichrome stain was used to demonstrate changes in collagen deposition of arterioles. The alpha-smooth muscle actin (alpha-SMA) expression in pulmonary arteries was measured by immunohistochemisty. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) content in pulmonary arteries were determined by the colorimetric method. The protein expressions of collagen I, NOX2 and NOX4 were analyzed by Real-time PCR and Western blot.. After the administration for 4 weeks, Ses could attenuate RVSP and mPAP induced by MCT, RV/ (LV + S) and ratio of RV to Tibial length, alpha-SMA and collagen I expressions and remodeling of pulmonary vessels and right ventricle. Meanwhile, Ses could obviously inhibit the expressions of NOX2, NOX4 and MDA content and increase T-AOC.. Sesamin could ameliorate pulmonary vascular remodeling induced by monocrotaline in PH rats. Its mechanism may be related to expressions of NOX2 and NOX4 expression and reduction in oxidative stress injury.

Topics: Animals; Dioxoles; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Hypertension, Pulmonary; Lignans; Lung; Male; Membrane Glycoproteins; Monocrotaline; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vascular Remodeling