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Role of altered mitochondrial metabolism in determining fibrosis in the pulmonary vasculature and right ventricle in pulmonary arterial hypertension

Canadian Vascular Network |Réseau canadien vasculaire

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Role of altered mitochondrial metabolism in determining fibrosis in the pulmonary vasculature and right ventricle in pulmonary arterial hypertension

Lian Tian, Queen’s University

Supervisor: Stephen Archer, Queen’s University

Pulmonary arterial hypertension (PAH) is characterized by sustained increases in resting mean pulmonary artery pressure (mPAP) of >25 mmHg. While the elevated mPAP is due to vascular obstruction and constriction, the prognosis in PAH is determined by the response of right ventricle (RV). In-hospital mortality rates exceed 14% in PAH patients who are admitted to hospital with RV failure (RVF). Some patients with PAH are adaptive remodelers and develop RV hypertrophy (RVH) while retaining RV function; others are maladaptive remodelers and rapidly develop RVF. Maladaptive RVH is characterized by RV dilatation and fibrosis, which is associated with mitochondrial metabolic abnormalities in RV, including a shift to aerobic glycolysis. The causes of maladaptive remodeling and RVF are understudied and not predicted by the hemodynamic severity of the pulmonary hypertension or the RV mass. Fibrosis in both conduit PAs and the RV occurs in PAH patients and rodent models and reduces vascular compliance, which may contribute to RVF development. In the proposed studies we will evaluate changes in RV function, metabolism and fibrosis in adaptive versus maladaptive RVH models. The temporal relationship of change in RV metabolism and RV fibrosis will be ascertained in vivo and in fibroblasts isolated from large PAs and the RV. By isolating fibroblasts for metabolic study and transcriptional profiling we will ascertain whether these cells share the transcriptional and metabolic derangements we have discovered in RV myocytes and PA smooth muscle cells. We will also assess whether metabolic therapies that restore glucose oxidation by activating pyruvate dehydrogenase reduce PA and RV fibroblast proliferation, decrease collagen deposition and improve RV function. This study will explore fibroblast metabolism as a potential novel therapeutic target in PAH. It will also increase our knowledge of the role of the altered mechanical properties of the conduit PA and RV in RVF development.