Abnormalities in the innate and adaptive immune system are key pathogenic factors in cardiovascular disease, including hypertension, atherosclerosis and cardiomyopathy. The current proposal focusses on macrophages, which contribute to inflammatory damage through multiple effector functions, e.g. pro- inflammatory cytokine release, inefficient removal of lipids and debris, matrix degradation and antigen presentation to T lymphocytes. In preliminary studies we have shown that macrophages from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce excess IL-1? and IL-6. Cytokine overproduction in patient-derived macrophages is correctable by restricting glucose or scavenging reactive oxygen species (ROS). We have pinpointed the underlying molecular mechanism to the enzyme pyruvate kinase M2 (PKM2), a redox-sensitive molecule, which as a tetramer functions as a cytoplasmic metabolite kinase and as a dimer acts as an inflammation-promoting nuclear protein kinase. In patients with atherosclerotic or hypertensive disease, PKM2 is primarily dimerized and imported into the nucleus, an abnormality that connects altered metabolic regulation with excess inflammatory immunity. In essence, in patients with cardiovascular disease, glucose overutilization fuels inflammatory macrophage functions through ROS-induced nuclear translocation of PKM2, where the enzyme promotes cytokine production and feed-forward activation of glycolysis; a pathology resembling the Warburg effect of cancer cells. Working closely with Project 1 and 3, Project 2 will define basic molecular mechanisms that couple metabolic and functional abnormalities in vascular inflammation.
Aimi ng for the discovery of actionable diagnostic and therapeutic targets in inflammatory immune responses, we will focus on the glucose-ROS- PKM2 pathway.
Specific Aim 1 will seek to mechanistically understand how ROS production and glycolytic flux determine the oligomeric state, cellular localization and function of PKM2.
Specific Aim 2 is devoted to a comparative metabolic and functional analysis of macrophages in coronary artery disease and in hypertension to dissect shared and selective pathologies. In an effort to understand how patient-derived macrophages are metabolically reprogrammed, this aim will utilize a novel epigenetic technique (ATAC seq) to identify poised genes and pioneer transcription factors.
In Specific Aim 3, we will reveal the role of PKM2 in regulating the spectrum of pathogenic macrophage functions and determine the impact of glucose addiction on T cell immunity (Th1, Th17, Treg and Thf immune responses).
Specific Aim 4 will explore whether molecular commonalities between inflammatory macrophages and cancer cells can be exploited for novel therapies in cardiovascular disease. In preclinical studies we will test whether small molecule inhibitors developed to treat the Warburg effect in cancer cells can be repurposed to suppress inflammation in cardiovascular disease.
Cardiovascular disease, including atherosclerosis and hypertension remain the primary cause of morbidity and mortality in the United States. Only recently has it become clear that the immune system by causing inflammation contributes to blood vessel disease, but therapies harnessing the role of immune cells in atherosclerosis and hypertension are insufficiently exploited. This project examines why patients with coronary artery disease and hypertension generate inflammatory macrophages and how sugar consumption and metabolic dysregulation contribute to the disease.
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