Involvement of fatty acid synthase in right ventricle dysfunction in pulmonary hypertension

Abstract Apart from pulmonary vascular resistance and right ventricle (RV) hypertrophy, metabolic dysfunction also plays a major role in pathophysiology of pulmonary hypertension (PH). Recently, we have shown that fatty acid synthase (FAS), an enzyme involved in de novo fatty acid synthesis, plays a pivotal role in PH as its inhibition was protective and decreased pulmonary vascular remodelling, RV pressure and hypertrophy and improved endothelial functions. However, the precise mechanism behind protective effect of FAS inhibition on right ventricle dysfunction associated with PH is not completely understood. Therefore, the present study delineated the mechanism of protective effect of FAS inhibition on RV dysfunction associated with PH. siRNA mediated inhibition of FAS reduced FAS expression, hypertrophy, inflammation, apoptosis, autophagy and improved the glucose oxidation, mitochondrial membrane potential and ATP level in hypoxic cardiomyocytes. In monocrotaline (MCT) treated rats, FAS inhibition by C75 (2 mg/kg, i.p., once a week from 21 to 35 days) decreased the expression and activity of FAS and palmitate level. C75 also improved cardiac functions and mitochondrial membrane potential leading to decreased apoptosis in RV of MCT treated rats. In conclusion, our study reveals that inhibition of FAS decreases RV hypertrophy and improves cardiac function associated with PH by perking up metabolic functions.