Abstract Body (Do not enter title and authors here): Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease with unmet medical needs. Patient outcomes primarily depend on the ability of the right ventricle (RV) to maintain adequate function, yet no therapy preventing RV dysfunction is currently available. Previous studies have demonstrated that patients with PAH exhibit an impaired fatty acid (FA) metabolism and RV steatosis. Furthermore, this RV lipotoxicity was associated with a substantial accumulation of the cardiotoxic sphingolipid ceramide. In this study, we utilized a novel rat model of severe mitochondrial dysfunction (MD) induced by humanized G206C mutation in the NFU1 protein to investigate the role of MD in the RV FA metabolism.
Hypothesis: We hypothesized that MD severely impairs FA metabolism, leading to the upregulated synthesis of cardiotoxic ceramides.
Methods: The RV functional analysis and mitochondrial respiration were assessed in the NFU1^G206C rats with a developed PAH phenotype and age-matched wild types (WTs). The FFA transporter expression level and cardiac lipotoxicity markers were compared in the isolated RV and left ventricle (LV) cardiomyocytes (CMs). To address the role of ceramides, we investigated the protective capacity of the inhibitor of dihydroceramide desaturase-1 (DES1), catalyzing the final step in the de novo ceramide synthesis.
Results: RV but not LV CMs showed impaired mitochondrial respiration in NFU1^G206C rats. Consistent with findings in PAH patients, these changes were associated with a significant RV steatosis and an increase in the expression of free FA transporter, CD36, and DES1, both observed explicitly in NFU1^G206C RV CMs. Treatment with a DES1 inhibitor (DES1i, 2.5 mg/kg i.p., every other day for 4 weeks) attenuated the PAH phenotype in NFU1^G206C rats (RV systolic pressure: WTs vs. NFU1^G206C vs. NFU1^G206C+DES1i; 23.8 ± 1.3 vs. 32.7 ± 3.7 vs. 27.1 ± 1.3 mmHg, p < 0.001 (ANOVA), N=5:), by inhibiting RV hypertrophy (Fulton Index: 0.27 ± 0.01 vs. 0.30 ± 0.01 vs. 0.27 ± 0.01, p < 0.05 (ANOVA), N=5) and improving mitochondrial function in CMs.
Conclusion: MD is a significant contributor to RV dysfunction, lipotoxicity, and enhanced ceramide synthesis. The protective effect of DES1 inhibition underscores the therapeutic potential of targeting ceramide pathways in PAH.