In line with the overall mission of the PPG, Project 1 addresses the role of inflammation, and specifically the role of macrophages in the vascular remodeling that characterizes hypoxic forms of pulmonary hypertension (PH). Observations in most forms of PH show that macrophages accumulate primarily in the adventitial and perivascular regions of the vessel. Strong preliminary data demonstrate that fibroblasts resident in the adventitia of PH vessels undergo significant metabolic changes leading to increases in intracellular NADH concentration and subsequent activation of the transcriptional repressor C-terminal binding protein 1 (CtBP1), a transcriptional redox sensor with high binding affinity for NADH. CtBP1 acts specifically to repress expression of anti-inflammatory genes including, hemoxygenase-1 (HMOX-1). These ?activated? fibroblasts recruit and activate macrophages toward a pro-inflammatory/remodeling phenotype largely through IL6, STAT3, HIF1 signaling and induction of aerobic glycolysis. We propose that both the pro-inflammatory fibroblast and fibroblast activated macrophage phenotype in hypoxic PH is driven by CtBP1. During hypoxia and/or in conditions of aerobic glycolysis we have shown that NADH-activated CtBP1 acts as a transcriptional co- repressor and complexes with DNA-binding transcription factors and histone modification enzymes (HDACs, HMTs). CtBP1 therefore links the metabolic status of the cell to specific coordination of gene transcription and, as we have shown, exerts a dominant role in determining cell behavior. We now address the novel hypothesis that CtBP1 drives the pro-inflammatory functions of fibroblasts in PH, leading to fibroblast-mediated macrophage activation. The inflammatory environment, caused by the interaction of fibroblasts and macrophages, leads to PH and pulmonary vascular remodeling. Our approach relies on in vitro and in vivo studies using lung adventitial fibroblasts and primary nave macrophages from hypoxic cows, rodents, and human controls and PH patients, and novel genetically modified mice.
AIM 1 : Determine the role of CtBP1 in ?locking? the fibroblast into a pro-inflammatory phenotype.
AIM 2 : Determine the role of HIF1 and CtBP1 in inducing the pro-inflammatory/-fibrotic phenotype of fibroblast-activated macrophages with the goal of blocking these pathways to prevent/reverse pulmonary vascular remodeling and PH.
AIM 3 : Determine if CtBP1 can be targeted in vivo to reverse PH. In conjunction with Projects 2 and 3 of this PPG, our investigations will ultimately provide key data in elucidating the role of inflammation as a cause/contributor, a bystander, or whether or when it is simply the end result of the disease process. This is a critical step to advance our understanding of chronic pulmonary vascular disease in order to significantly impact the clinical management of PH.
Inflammation is thought to play a fundamental role in the pathogenesis of pulmonary hypertension (PH). We have demonstrated that inflammatory cells accumulate mostly on the outer part of the blood vessel in PH. We show that cells resident in the outside of the vessel wall, fibroblasts, undergo changes that allow them to cause a prolonged and non-resolving accumulation of inflammatory cells in the vessel wall. The project is directed at elucidating the mechanisms and then designing pharmacologic therapies to abrogate the persistent accumulation of inflammatory cells by ?turning off? the fibroblasts.
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