Sex-dependent mitochondrial function of right ventricle in pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) is fatal and rapidly progressive disease with 5-year survival rate of ~37%. In PAH the elevated mean pulmonary artery pressure leads to increases in right ventricular (RV) afterload and pressure. As PAH progresses, RV hypertrophy occurs and eventually RV fails, leading to the death of PAH patients. Currently there is no effective therapy targeting RV in PAH.
Though the pathology in PAH begins with an obstructive vasculopathy in the pulmonary circulation, the prognosis in PAH is mainly determined by the response of the RV to the resulting pressure overload. RV failure is associated with mitochondrial metabolic abnormalities in the RV, notably mitochondrial fragmentation (fission) and a shift toward uncoupled aerobic glycolysis (Warburg metabolism). Mitochondrial metabolic function has been proposed to link to many observed molecular abnormalities and the resulting PAH phenotypes in both RV and lungs, and mitochondria has been placed at the center stage as many groups strive to understand the PAH pathogenesis and to develop novel, promising therapeutic targets.
Another important fact is the unexplained sex paradox in PAH. PAH occurs 2-4 fold more frequently in women compared to me; however, compared to men with PAH, women with PAH have better RV function and exhibit better survival. Estrogen is considered as an important factor to contribute to the pathobiology and the sex difference in PAH. While estrogen is thought to cause more women than men to develop PAH, it is also thought to be protective in women with PAH. Literature has extensive studies on the role of estrogen in the sex difference in the lungs in PAH, but the role of estrogen on RV function is little studies.
Studies have shown that there is interaction between estrogen and mitochondria. While mitochondria can mediate estrogen production, estrogen can also regulate mitochondrial function. The estrogen-mediated mitochondrial function in RV and thus RV function from both male and female PAH and the sex difference are not well studied.
Aims: The goal of this project is to identify novel, promising therapeutic targets for RV in PAH patients of both sexes.
Objectives: We will use two well-validated preclinical animal models of PAH, i.e., the monocrotaline and Sugen/hypoxia rat models, and study the mitochondrial function of RV from both male and female PAH rats and the molecular pathways involving estrogen and mitochondria. In addition, human tissues from PAH patients will be studied to potentially validate the proposed therapeutic targets from preclinical models.
Techniques used:
Rodent animal surgery, hemodynamic measurement and tissue harvest
Cell isolation and culture and siRNA approach
Cellular biology assessments including PCR and immunoblotting
Immunohistochemistry
Confocal Imaging
Proteomics