Acetate mitigates cardiac mitochondrial dysfunction in experimental model of polycystic ovarian syndrome by modulating GPCR41/43 and PROKR1.

The role of short chain fatty acid, acetate in cardiac mitochondrial dysfunction especially in PCOS individuals is unknown. Therefore, the present study investigated the modulatory role of GPCRs (41 and 43) by acetate on cardiac mitochondrial status in PCOS rat model. Eight-week-old female Wistar rats were randomly allotted into four groups (n = 5). Polycystic ovarian syndrome was induced by administering letrozole (1 mg/kg p.o.) once daily for 21 days, thereafter the animals were treated with 200 mg/kg (oral gavage) of acetate for six weeks. Letrozole-induced PCOS rats showed elevated circulating testosterone and anti-mullerian hormone, with multiple ovarian cysts. In addition, these rats also manifested insulin resistance, hyperinsulinemia, and increased plasma triglyceride (TG), TG/HDLc and decreased HDLc, as well as elevated level of cardiac TG, glycogen, glycogen synthase, and plasma/cardiac NF-kB, TNF-α, and SDF-1. Cardiac MDA and caspase-6 increased, while plasma/cardiac NrF2 decreased in PCOS animals. A decrease in mitochondrial ATP synthase, ATP/AMP ratio, CPT2 and SDH, and increased HDAC2 were observed in PCOS rats with decreased level of GPCR 41 and 43 when compared with control. Immunohistochemical evaluation of cardiac tissue also showed decrease expression of PROKR1 in PCOS rats compared with control rats. However, treatment with acetate reversed these systemic, cardiac and mitochondrial anomalies. The present results suggest the therapeutic benefit of acetate, an HDAC2i against cardiac mitochondrial dysfunction in PCOS rat model, by attenuating cardiac inflammation, oxidative stress and apoptosis and these effects are accompanied by modulation of GPCR41 and 43 as well as increased expression of PROKR1.