| BACKGROUNDPulmonary arterial hypertension (PAH) is a progressive condition characterized by elevated pulmonary vascular resistance, leading to the increased of pulmonary circulation pressure and right ventricular (RV) failure. Pulmonary vascular remodeling is the basic pathologic characteristics of PAH, which is involved in proliferation of pulmonary arterial smooth muscle cells (PASMCs), endothelial function disorder and an increase in the extracellular matrix. The progress in PAH increases afterload on the RV, which promotes right ventricular hypertrophy and right heart failure in the end. Pulmonary vascular and RV remodeling are the central stages for PAH development and major reasons account for poor prognosis for PAH patients. Current drugs for PAH therapy include calcium channel blockers, endothelin receptor inhibitors, phosphodiesterase5inhibitors, prostacyclin analogues and so on. Most of the drugs are vasodilators, which target pulmonary artery to improve vascular diastole and attenuate vascular remodeling. These therapeutic approaches mainly show some therapeutic effects on symptomatic relief but lack of specificity. Recent studies have indicated oxidative stress (OS) as a mediator of PAH and contributes greatly to PAH cardiovascular remodeling. Therefore, it is a novel strategy to use antioxidant drugs for PAH therapy.Resveratrol (trans-3,5,4’-trihydroxystillbene, RSV), a polyphenol compound found in grapes and peanuts, has been shown to exhibit a wide range of pharmacological activities, including anti-inflammatory, cancer prevention, antioxidant, antiproliferative, and antifibrotic capacities. Recent studies have indicated that RSV can inhibit pulmonary vascular remodeling and right ventricular hypertrophy induced by monocrotaline (MCT) in rats.(E)-3,5,4’-trimethoxystilbene (BTM-0512) is the methylated derivative of RSV. The absorbance rate of BTM-0512is higher than RSV, and its half-life is extended. In the present study, using a rat model of hypoxia-induced PAH, the effects of BTM-0512on pulmonary vascular and right ventricular remodeling and the underlying mechanisms were explored.METHODSRats were maintained under hypoxia (10%O2) for4weeks to induce hypoxia PAH model.60Male Sprague-Dawley rats (180-220g) were randomly divided into6groups (n=10):the control group, the hypoxia group, the vehicle group, the low dose BTM-0512group (5mg/kg, BTM-L), the high dose BTM-0512group (10mg/kg, BTM-H) and the resveratrol group (25mg/kg, RSV). The animals were treated with drugs for4weeks. At the end of experiments, the RVSP, mPAP and the ratio of RV to (LV+IVS) or the RV to the length of the tibia, the plasma levels of hydrogen peroxide and superoxide anion, the mRNA and protein levels for NOX2, NOX4and VPO1in pulmonary arterial or right ventricular tissues samples were determined.RESULTS1. RVSP and mPAP of PAH rats induced by hypoxia were higher than that of normoxia rats. The thickness of pulmonary arterial wall and the right ventricular remodeling index in PAH rats was increased. These changes were reversed by BTM-0512treatment.2. Compared with control group, the levels of NOX2, NOX4, VPO1mRNA and NOX2, VPO1protein expression were significantly increased in right ventricular of hypoxia group. These changes were attenuated by BTM-0512treatment.3. Compared with control group, the levels of NOX4, VPO1mRNA and NOX2, NOX4protein expression were significantly increased in pulmonary arteries of hypoxia group. These changes were attenuated by BTM-0512treatment. CONCLUSION1. BTM-0512is able to decrease RVSP and mPAP induced by hypoxia.2. BTM-0512is able to inhibit pulmonary vascular remodeling induced by hypoxia. The mechanism is related to reducing the expression of NOX2, NOX4and VPO1in pulmonary arteries tissue.3. BTM-0512is able to inhibit right ventricular remodeling induced by hypoxia. The mechanism is related to downregulation of the expression of NOX2, NOX4and VPO1in right ventricular tissue. |
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