Grant: Project Grant

Right ventricular failure (RVF) is the leading cause of death in people with pulmonary arterial hypertension (PAH), and current therapies do not target the right ventricle (RV). Blockage and constriction of the pulmonary arteries (the blood vessels in the lung) increase the resistance to blood flowing out of the RV in PAH. However, this increase in RV afterload alone is insufficient to drive RVF. While some PAH patients adapt to severe PAH and high afterload without developing RVF, in others, particularly those with inflammatory connective tissue diseases, RVF occurs rapidly after diagnosis. We showed that RVF in PAH (patients and rodents) occurs partly because of inflammation mediated by activation of the NLRP3 inflammasome in RV macrophages. These activated macrophages damage mitochondria in heart muscle cells. We propose that mitochondria in RV cells are both a source and sensor of proinflammatory damage-associated molecule patterns (DAMPs), such as mitochondrial DNA (mtDNA). The recognition of mtDNA by pattern recognition receptors (PRRs) in cardiomyocytes and macrophages activates inflammatory pathways leading to RVF. To identify the cellular and molecular mechanisms involved in this process, we will study 1) the role of NLRP3 inflammasome in controlling RVF in PAH using mice in which NLRP3 has been deleted. We will assess the benefits of eliminating this inflammatory pathway. We will also study 2) the role of increased mitochondrial division (fission) in cardiomyocytes and macrophages in generating mtDNA and triggering inflammation. We will explore 3) the role of the RIG1-MAVS pathway in sensing mtDNA in cardiomyocytes and triggering inflammation in RVF using mice, rats, and human tissues. This proposal will reveal mechanisms of mitochondrial damage in the PAH RV and identify how mitochondria participate in inflammation and RVF. We will also identify novel targets for RV-specific therapeutics.