Commentary: The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension

Commentary: The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a progressive and irreversible lung disease that reduces survival. Importantly, the pulmonary arteries carry blood from the heart to the lungs; however, in PAH pulmonary vessels are remodeled causing abnormal constriction and a pressure change that prevents an adequate supply of oxygen delivered to the lung tissue (Farber and Loscalzo, 2004). PAH is categorized as a pulmonary artery pressure greater than 25 mmHg, with various factors contributing to the pathogenesis of the disease, including higher levels of endothelin-1, decreased nitric oxide (NO) synthase expression, and inhibition of the prostacyclin pathway which leads to decreased relaxation and induced proliferation of pulmonary artery smooth muscle cells (PASMCs) (McLaughlin and McGoon, 2006). Inflammation, toxins, lack of oxygen, and the deregulation of coagulation factors, are associated with endothelial cell dysfunction in PAH (McLaughlin and McGoon, 2006). The main pathologic changes associated with PAH include vasoconstriction, endothelial and smooth-muscle cell proliferation, thrombosis, and pulmonary remodeling (Farber and Loscalzo, 2004). PAH may eventually cause an enlarged right ventricle and compressed left side of the heart, leading to right ventricular heart failure in severe cases (McLaughlin and McGoon, 2006). It has also been theorized that glycolysis and oxidative phosphorylation play a role in patients with PAH, mediating cell proliferation, migration, and angiogenesis (Chen et al., 2014). Individuals afflicted with PAH have dyspnea, angina, fatigue, and increased pulmonary resistance (McLaughlin and McGoon, 2006). Without medical treatment, the survival rate is estimated to be less than 3 years after diagnosis (Cottrill and Chan, 2013). Thus, PAH is a serious illness and can be fatal, which signifies the importance of finding novel targets that can control and regulate this disease (Beckham et al., 2013; Chen et al., 2014). Although current treatment options for PAH include phosphodiesterase-5 inhibitors, prostanoids, calcium channel blockers, endothelin receptor antagonists, diuretics, oxygen therapy, and surgical procedures, such as atrial septostomy, these treatments only delay the progression of the disease (McLaughlin and McGoon, 2006; Tuder et al., 2012). Thus, a cure for PAH remains to be elucidated. Interestingly, recent research suggests that two important kinases, sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2), are primary therapeutic targets for pulmonary hypertension (Cottrill and Chan, 2013; Chen et al., 2014). It is reported that SphK1 is a promoter for tumor progression, invasion, and metastasis in gastric, prostate, colon, breast, and small cell Bhavanam …