Diabetic cardiomyopathy (DCM) is a chronic multifactorial complication of type-2
diabetes mellitus, leading to
heart failure. A combination of multifaceted
therapeutics for the management of DCM is needed. Here, we investigated the combined effect of
syringin and
tilianin on DCM by evaluating cardiac function,
inflammation, oxidative stress, apoptosis and mitochondrial function, and explored the contribution of TLR4/NF-κB/NLRP3 and PGC1α/
SIRT3 pathways in diabetic rats and hyperglycemic-H9c2 cells.
Syringin and
tilianin (50 and 60 mg/kg, i.p, respectively) were administered for eight weeks, individually or in combination, to healthy and type-2 diabetic Sprague-Dawley rats. Myocardial function was recorded using a carotid
catheter, mitochondrial and histopathological changes were evaluated by fluorometric and staining methods, cardiac markers and signaling pathways'
proteins expression were measured through ELISA and immunoblotting. In comparison to individual treatments, combination of
syringin and
tilianin effectively exerted
antidiabetic effects and improved cardiac function and DCM markers, reduced NLRP3/IL-6/IL-1β/TNF-α expression, and suppressed diabetes/hyperglycemia‑induced oxidative stress in rats' heart and H9c2 cells, as demonstrated by decreased
8-isoprostane, and increased
superoxide dismutase-2 levels. Mitochondrial membrane depolarization and ROS production were inhibited, and
caspase-3 and Bax/Bcl2 expression downregulated by combination
therapy. Combined treatment markedly inhibited up-regulation of TLR4, MyD88 and NF-κB in diabetic rats. Finally, inhibition of PGC1α/
SIRT3 pathway by 3-TYP in hyperglycemic H9c2-cells reversed the beneficial effects of combination
therapy on cardiomyocytes injury and NF-κB/NLRP3/IL-1β expression, without affecting TLR4/MyD88 expression.
Syringin plus
tilianin synergistically inhibited the diabetes-induced cardiac functional, biochemical and histopathological changes in DCM. Crosstalk between TLR4/NF-κB/NLRP3 and PGC1α/
SIRT3/mitochondrial pathways contributed to this protection.