افزایش فشار خون ریوی: جنبه های مولکولی مداخله درمانی Pulmonary Hypertension: Molecular Aspects of Current Therapeutic Intervention and Future Direction

Introduction Pulmonary hypertension (PH) is a diverse group of fatal disorders characterized by a sustained increase in pulmonary artery pressure and vascular resistance due to pulmonary artery hyper-constriction (Cogolludo et al., 2007). The elevated blood pressure in the pulmonary artery leads to cardio-muscular stress followed by gradual enlargement of the right ventricle. Similarly, the reduced production of vasodilator including prostacyclin (PGI2) and nitric oxide (NO) or consequent increase in endogenous vasoconstrictors like endothelin-1 (ET-1) and thromboxane A2 in pulmonary circulation leads to pulmonary endothelial dysfunction (Cogolludo et al., 2007). The availability of endothelial derived relaxation factor (EDRF) ‘NO’ was noted to be reduced in the pulmonary circulation due to impaired activation of endothelial nitric oxide synthase (eNOS) (Chester and Yacoub, 2014). Moreover, increased level of serotonin endorses the pulmonary artery smooth muscle cell (PASMC) proliferation, vasoconstriction and local microthrombosis (Lang and Madani, 2014). Patients with PH have high levels of serotonin in circulation that indicate the influence of serotonin on induction of PH (MacLean et al., 2000). Indeed, several potential sites including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, soluble gunanyl cyclase stimulators, Rho kinase inhibitors, serotonin receptor antagonist and serotonin transporter blockers, statins, peroxisome proliferator activated receptor agonist, calcium channel blockers, potassium channel openers, tyrosine kinase inhibitors are currently target to impede the vulnerability of PH. Preclinical evidence implicate the role of Rho-kinase in the pathogenesis of pulmonary hypertension (JasińskaStroschein et al., 2014). Rho kinase suppresses the myosin phosphatase and augments the contractility of pulmonary artery smooth muscle cells (PASMC) in rats. Transient receptor potential channels (TRPC) has also found to be over expressed in pulmonary hypertension and influence the smooth muscle cell (PASMC) proliferation and pulmonary vascular medial hypertrophy (Malczyk et al., 2017). Certainly, increased oxidative stress contributes to pulmonary vascular cell growth and right ventricular hypertrophy (Sharma et al., 2015). Evidence suggests that reactive oxygen species (ROS) exceeds the quenching capacity of antioxidant mechanisms of the cell and protein carbonylation may be involved in the pathology of PH (Wong et al., 2013; Sharma et al., 2015).