Abstract Rationale Pulmonary arterial hypertension (PAH) is a fatal disease characterized by remodeling of small pulmonary arteries, leading to elevated right ventricular (RV) afterload, hypertrophy, and dysfunction. While RV failure is the primary cause of mortality in PAH patients, no current therapies adequately protect the RV function. We postulate that mitochondrial dysfunction (MD) acts as a central driver of maladaptive lipid accumulation, promoting RV steatosis and the buildup of cardiotoxic ceramides that precipitate RV failure. Methods We assessed the effects of MD on RV metabolism using rats with a pathogenic NFU1 point mutation (NFU1G206C), which impairs mitochondrial respiration and induces a spontaneous PAH phenotype with severe vasculopathy and RV dysfunction. The discoveries in the NFU1G206C model were additionally validated using a classical pulmonary artery banding (PAB) model of chronic RV pressure overload. To test the therapeutic potential of targeting ceramide synthesis, we inhibited delta-4-desaturase sphingolipid 1 (DES1), the rate-limiting enzyme in ceramide synthesis, using the DES1-specific inhibitor Compound 34 (DES1i, 2.5 mg/kg, i.p., every other day for 4 weeks). Cardiac function was evaluated by pressure-volume (PV) loop analysis. RV tissues and isolated cardiomyocytes (CMs) from control, diseased, or treated rats were analyzed for mitochondrial respiration, free fatty acid (FFA) transport and oxidation (FAO), ceramide enzyme expression, and lipid accumulation. Results RV CMs from NFU1G206C rats showed severely impaired mitochondrial respiration, elevated FFA transporter expression, and dysfunctional FAO, leading to increased FFA uptake. This dysregulated lipid metabolism was associated with marked RV steatosis, elevated DES1 expression, and ceramide overload. Inhibition of DES1 improved mitochondrial function and significantly reduced cardiotoxic ceramide accumulation (∼65% in NFU1G206C, ∼50% in PAB). Lipidomic profiling revealed a robust reprogramming of the cardiac lipid landscape in both DES1i-treated models. This shift was accompanied by improved mitochondrial membrane dynamics, enhanced ATP generation, diminished lipotoxic stress, suppression of pro-hypertrophic signaling, and heightened cardiac resilience to mechanical and metabolic stress. The shift of RV into a cardioprotective metabolic state preserved RV function and blunted maladaptive RV hypertrophy (RV/LV+S: NFU1 vs NFU1+DES1i; 0.31 ± 0.03 vs 0.27 ± 0.02, p 0.05, N = 5; PAB vs PAB+DES1i; 0.34 ± 0.07 vs 0.29 ± 0.03, p 0.05, N = 4-5). Conclusion Our study identifies MD as a key driver of ceramide-driven lipotoxic remodeling in the RV. Pharmacologic inhibition of ceramide synthesis alleviates lipid overload and reprograms RV metabolism toward a cardioprotective state, mitigating RV hypertrophy and preserving RV function across different experimental models. This abstract is funded by: NHLBI, AHA
Niihori et al. (Fri,) studied this question.