Abstract 15711: Mitochondrial Metabolic Remodeling of Cardiac Fibroblasts Promotes Right Ventricular Fibrosis in Pulmonary Arterial Hypertension
Introduction: In pulmonary arterial hypertension (PAH), fibrosis of pulmonary arteries (PAs) and the right ventricle (RV) is associated with reduced PA and RV compliance, respectively. The role of fibrosis in PAH is under-appreciated. In both PA and RV there is mitochondrial-metabolic remodeling that drives cell proliferation and apoptosis-resistance thereby promoting PAH.
Hypothesis: RV fibroblasts undergo changes in mitochondrial-metabolic phenotype, specifically increased mitochondrial fission and a metabolic shift to aerobic glycolysis, and this mitochondrial-metabolic abnormality drives fibroblast proliferation and promotes RV fibrosis.
Methods: Rats received a single injection of monocrotaline (MCT) or saline. Rats received either control drinking water or water containing the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) beginning day 7 post injection (n>5/group). At week-4, PAH was confirmed by echocardiography. Vimentin (+) RV fibroblasts were enzymatically isolated. The following measurements were made in cells cultured in the presence or absence of DCA: proliferation, metabolism, mitochondrial fragmentation, pyruvate dehydrogenase (PDH) activity and the expression of Glut1, PDK, collagen and procollagen.
Results: Compared to control, MCT rats displayed more fibrosis in RV tissue. MCT-derived RV fibroblasts displayed mitochondrial fragmentation and had higher proliferation rate. Compared to control, MCT-derived RV fibroblasts also had lower oxygen consumption rate (OCR) and decreased PDH activity. DCA increased OCR in MCT RV fibroblasts. qRT-PCR showed upregulation of Glut1, PDK 1 & 3, and collagen III in MCT vs. control RV fibroblasts. Procollagen III protein was also increased in MCT vs. control RV fibroblasts. DCA reduced collagen production in MCT RV fibroblasts in vitro and improved RV function of MCT rats in vivo, as indicated by reduced RV free wall thickness and increased tricuspid annular plane systolic excursion.
Conclusions: In experimental PAH RV fibroblasts manifest increased mitochondrial fragmentation and a shift to aerobic glycolysis that drive collagen production and fibrosis. These changes can be therapeutically targeted with DCA resulting in improved RV function.
Author Disclosures: L. Tian: None. A. Dasgupta: None. D. Wu: None. K. Chen: None. J. Mewburn: None. S.L. Archer: None.
- © 2016 by American Heart Association, Inc.