Amifostine attenuates pressure overload-induced cardiac hypertrophy and metabolic remodeling via the SIRT1/PPAR-α axis in rats.

Pathological cardiac hypertrophy induced by chronic pressure overload is accompanied by significant metabolic disturbances, including impaired myocardial lipid metabolism. This study ascertained whether the cytoprotective agent amifostine (WR-2721) exerts cardioprotective effects along pressure overload-induced remodeling and whether these effects are linked to modulation of the SIRT1/PPAR-α axis. Male Wistar rats (n = 24) were assigned to Sham, abdominal aortic constriction (AAC), and AAC + amifostine (200 mg/kg, i.p., weekly for 8 weeks) groups, with amifostine administered concurrently with hypertrophic stress. The cardiac structure and function were appraised using echocardiography and histological analyses, with the expression of SIRT1, PPAR-α, and key regulators of lipid metabolism examined by Western blotting. Amifostine treatment was associated with attenuation of pressure overload-induced cardiac hypertrophy, reflected by lower heart and lung weight ratios, preservation of functional indices, and diminished myocardial fibrosis. At the molecular level, amifostine administration was accompanied by relative normalization of SIRT1 and PPAR-α expression, elevated levels of fatty acid oxidation-related proteins, and suppression of lipogenic markers. These findings suggest that amifostine mitigates pressure overload-induced cardiac remodeling and is associated with improved myocardial metabolic homeostasis, accompanied by favorable changes in the expression of SIRT1, PPAR-α, and lipid metabolism-related proteins. While these observations support the potential involvement of the SIRT1/PPAR-α signaling pathway, further mechanistic studies are required to establish its causal role in mediating the cardioprotective effects of amifostine.