Naringenin Attenuates Diabetic Cardiac Injury via SIRT1 Activation in Streptozotocin-Induced Rats.

OBJECTIVE

Diabetic cardiomyopathy (DCM) lacks targeted therapies. This study investigated naringenin (NAR), a citrus flavonoid, in a streptozotocin (STZ)-induced diabetic rat model with cardiac complications, focusing on SIRT1-mediated mechanisms.

METHODS

Rats (n = 8/group) included control, NAR, DCM, DCM + NAR, and DCM + NAR + EX-527 (SIRT1 inhibitor). After 8 weeks, metabolic profiles, cardiac function, histopathology, oxidative stress (Nuclear Factor Erythroid-Related Factor 2 [Nrf2], MDA, SOD, and GSH), inflammation (nuclear factor kappa B [NF-κB], TNF-α, and IL-6), apoptosis (Bax/Bcl-2 and Caspase-3), fibrosis (transforming growth factor beta [TGF-β] and Smad2), and SIRT1 signaling were analyzed.

RESULTS

NAR exhibited hypoglycemic effects, stimulated the release of insulin, and enhanced the lipid profile, thus maintaining the structural integrity of cardiomyocytes and preventing an increase in heart weight, while also restoring the histomorphology in DCM rats. Moreover, NAR influenced both systolic and diastolic blood pressure; reduced serum levels of CK-MB, BNP, and troponin T; downregulated the activity of TGF-β, Smad2, and Caspase-3; and decreased the Bax/Bcl-2 ratio. Crucially, NAR upregulated SIRT1 and modulated the levels of Nrf2, NF-κB, Smad2, and Forkhead Box Protein O1 (FOXO1) in the cardiac tissues of the DCM group. These findings were associated with a significant reduction in oxidative stress and inflammation, alongside diminished NF-κB activity, while promoting Nrf2 activity and Bcl-2. Importantly, the effects of NAR were counteracted by EX-527.

CONCLUSION

NAR protects against DCM primarily through SIRT1 activation, integrating hypoglycemic, antioxidant, anti-inflammatory, antifibrotic, and antiapoptotic actions. SIRT1 represents a promising target for flavonoid-based DCM therapy.