Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance that can eventually lead to right ventricular failure and death. In systemic sclerosis (SSc), PAH is a leading cause of morbidity and mortality. Moreover, patients with SSc-PAH have a poorer prognosis than patients with idiopathic PAH. To improve treatment options for SSc-PAH, a better understanding of SSc-PAH pathogenesis is needed. Although the exact pathophysiology of PAH is unknown, abnormal cellular metabolism caused by altered mitochondrial dynamics, is now considered an important contributor to pathological alterations in PAH. During the prior grant period, we demonstrated increased endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in circulating immune cells (PBMCs) from SSc patients with limited disease (lcSSc), with even higher levels in lcSSc-PAH patients. We also demonstrated highly fragmented mitochondria in lcSSc PBMCsM extending these studies to lungs from SSc-PAH patients undergoing transplantation, we observed highly increased UPR markers in endothelial cells (EC) and macrophages and evidence of increased oxidation. Given the complex nature of PAH, a therapeutic agent capable of modulating several key pathways would be an attractive addition to the treatment regimen of PAH. As a possible candidate, we have focused on dimethyl fumarate (DMF), an agent that augments the intrinsic cellular antioxidant response and was recently approved (Tecfidera) for treatment of multiple sclerosis. Using the rodent-hypoxia model of PH, we found DMF prevented and reversed hemodynamic changes, muscularization of pulmonary vessels, and right ventricular hypertrophy. DMF also attenuated lung damage caused by oxidative stress and reduced immune cell infiltration into lungs of treated mice. To translate these results to human SSc-PAH, we propose: 1) Determine the role of altered mitochondrial dynamics on activation of immune cells in lcSScM 2) Determine the molecular characteristics of freshly isolated PAEC from lcSSc patients with and without PAH undergoing right heart catheterizationM and 3) Determine the effect of DMF on the function of distal resistance pulmonary arteries from explanted lungs of patients with SSc-PAH undergoing transplantation. These complementary studies will develop better understanding of the role of the redox state in the pathogenesis of SSc-PAH, validate anti-oxidants, such as DMF, as potential treatment for this entity, and develop collaborative disease models between Boston University and the University of Pittsburgh Medical Centers, two expert centers with long-standing interest in SSc and SSc-PAH.
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