Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a tetracyclic antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death (McLaughlin et al, 2018)
MCT was purchased from Biopurify Phytochemicals Ltd. (Chengdu, China) and dissolved in normal saline with 20% absolute ethanol (v/v) to a final concentration of 12 mg/mL. 50 mM stock solution of maprotiline was dissolved in DMSO, and stored at −80◦C
Prostacyclin, ET antagonists, and phosphodiesterase type 5 inhibitors are the primary drugs to improve the quality of life of PAH patients and alleviate symptoms (Jasinska-Stroschein and Orszulak-Michalak, 2014; Mercurio et al, 2018)
Summary
Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death (McLaughlin et al, 2018). Selexipag is developed by Actelion as an agonist of the prostacyclin receptor for the treatment of PAH, which leads to vasodilation in the pulmonary circulation (Sitbon and Morrell, 2012; Ghosh et al, 2016). It can be used as a vascular modulator in the development of PAH and provides symptomatic relief, but it fails to fully reverse the Abbreviations: HPASMCs, human pulmonary artery smooth muscle cells; MCT, monocrotaline; mPAP, mean pulmonary arterial pressure; NO, nitric oxide; PAH, pulmonary arterial hypertension; RV/BW, right ventricular/body weight; RV/LV+S, right ventricular/left ventricle + septum; RVH, right ventricular hypertrophy; RVSP, right ventricular systolic pressure; SD, Sprague-Dawley; sGC, soluble guanylate cyclase; SPR, surface plasmon resonance; WA, wall area; WT, wall thickness
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