Macrophage Metabolism in Pulmonary Arterial Hypertension (PAH): Implications for Right Ventricular Failure
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Authors
Jefferson, Lindsay
Date
2025-08-26
Type
thesis
Language
eng
Keyword
Metabolism , Immunometabolism , Pulmonary Arterial Hypertension , Right Ventricle Failure
Alternative Title
Abstract
Rationale: Pulmonary arterial hypertension (PAH) is an obliterative pulmonary vasculopathy characterized by right ventricular (RV) hypertrophy, often leading to RV failure (RVF). RVF in PAH is associated with an increase in monocyte-derived inflammatory macrophages in the RV. Most disease-relevant cell types in PAH exhibit a metabolic shift towards uncoupled glycolysis. Although inflammatory macrophages in some diseases exhibit a pro-glycolytic phenotype, it is unknown whether uncoupled glycolysis occurs in RV macrophages in PAH, and if so, whether it determines their inflammatory phenotype.
Hypothesis: A) Increased uncoupled glycolysis in RV macrophages underlies their inflammatory phenotype in PAH. B) Uncoupled glycolysis in PAH macrophages is driven by the activation of pyruvate dehydrogenase kinase (PDK) and HIF-1α. C) The inhibition of uncoupled glycolysis using dichloroacetate (DCA), a PDK inhibitor, restores glucose oxidation in macrophages and promotes an anti-inflammatory phenotype, reducing RVF.
Methods: PAH was induced in male Sprague-Dawley rats using monocrotaline (MCT). RV sections were stained to detect CD68+ macrophages expressing pro-glycolytic and pro-inflammatory markers. The expression of these markers was also measured in bone marrow-derived macrophages (BMDMs) from control and MCT rats using western blot and qRT-PCR. Mitochondrial metabolism and glycolysis were assessed in BMDMs using micropolarimetry. DCA was administered in MCT rats, and the effects on hemodynamics and immunometabolism were evaluated. Values were expressed as mean±SEM and statistically analyzed using parametric and nonparametric tests, as appropriate.
Results: RV Macrophages in MCT rats had increased expression of PDK1 (p=0.0013), GLUT1 (p=0.0060), and HIF-1α (p=0.0075) vs. controls. MCT BMDMs were primed towards an inflammatory phenotype with elevated His48 positivity (p=0.0247) and NFκB protein expression (p=0.0050) vs. controls. MCT BMDMs exhibited a pro-glycolytic phenotype, with increased PDK3 expression (p=0.0177). In vivo, DCA improved cardiac index in MCT rats. Ex vivo, DCA reduced His48 positivity in BMDMs (p=0.0181).
Conclusion: Macrophages from MCT-PAH rats exhibit an inflammatory, glycolytic phenotype. The shift towards uncoupled glycolysis in MCT macrophages is mediated by PDKs. Macrophage-induced inflammation is driven by metabolic activation of HIF-1α and NFκB. In vivo DCA treatment enhanced RV function independent of RV macrophage quantity. Immunometabolism in RV macrophages in PAH may offer a new therapeutic target.