Fatty acid synthase inhibition offers protection against pressure-induced cardiac hypertrophy.

Disturbed cardiac metabolism is an important aspect of the pathology of Cardiac hypertrophy (CH) which precede Heart failure (HF). Studies have shown a higher rate of De novo lipogenesis in HF and its inhibition has been protective. However, its role in CH still needs further clarification. For in vitro studies, Phenylephrine (PE) was used to induce CH in adult human ventricular cardiomyocytes (AC16). For in vivo studies, 2 kidney 1 clip (2K1C) and Transverse aortic constriction (TAC) models of rat were used. Fatty acid synthase (FAS), key enzyme of lipogenesis was inhibited using FAS si RNA (30 nM) and C75 (2 mg/kg, i.p. once a week for 8 weeks) in vitro and in vivo respectively. Echocardiography and histochemical staining were used to observe cardiac remodeling. Western blotting, Seahorse analysis, fluorescence microscopy and FACS were performed to detect metabolic alterations, mitochondrial dysfunction, protein synthesis and hypertrophy. We observed increased expression and activity of FAS in PE-exposed AC16 and 2K1C and TAC models of rats. Inhibition of FAS decreased hypertrophy, protein synthesis by malonylation of mTOR, apoptosis, glycolysis, and oxidative stress and restored oxidative phosphorylation in AC16 cells. In rats, FAS inhibition prevented cardiac remodelling in 2K1C and TAC models. It also increased ATP, restored mitochondrial ROS and membrane potential in the TAC model of rats. Our results demonstrated that FAS activity was modulated during CH, and inhibiting it prevented cardiac remodelling and mitochondrial dysfunctions. The findings, therefore, suggest that inhibiting FAS may be a new therapeutic approach to treating CH patients.