Reducing Reactive Lipids Improves Cardiac Metabolic and Diastolic Function in Pulmonary Hypertension Models

BackgroundReactive oxygen species are increased across most pulmonary hypertension (PH) etiologies, resulting in increased reactive lipid dicarbonyls, which form protein adducts and impair mitochondrial function. We hypothesized that reducing reactive lipids would reduce right ventricular systolic pressure (RVSP) and improve cardiac function by eliminating protein-lipid damage feedback loops. MethodsWe used 2-hydroxybenzylamine (2-HOBA) to scavenge reactive lipids in three complimentary mouse models of PH: AKR-high fat diet (HFD, metabolic stress), LNAME-HFD (cardiometabolic syndrome), and pulmonary artery banding (PAB, load stress). Cardiac function was measured by echocardiography and catheterization. RV energy metabolism was determined by oxygraphy. Mass spectrometry analyzed lipids and ceramides; O-link and RNA-Seq evaluated proteomic and gene expression in lungs, RV, and LV. ResultsReducing reactive lipids with 2-HOBA resulted in a [~]10% reduction in RVSP, reduced diastolic dysfunction, reduced plasma lipids and ceramides, and normalized RV fatty acid oxidation that was severely impaired in the AKR-HFD and PAB models. Proteomic and RNA changes in the lungs, RV, and LV suggested reduced oxidative damage and inflammatory signaling and altered developmental and actin organization signaling; these changes are plausibly associated with the improved adaptation. Some changes were sex specific, including a 4x higher cardiac fatty acid content in males than females. ConclusionsReactive lipid scavenging improves cardiac metabolic and diastolic function and pulmonary vascular resistance through restoration of mitochondrial function and reduced oxidative protein damage. The magnitude of hemodynamic improvement combined with substantial diastolic function improvement suggests clinical potential, particularly for PH patients with metabolic comorbidities.