Icariin attenuates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome through SIRT3-mediated TFAM deacetylation

Introduction: Icariin (ICA), a major flavonoid isolated from the traditional oriental herbal medicine Epimedium, exhibits various pharmacological activities, including anti-inflammatory and antioxidant properties. It has been demonstrated in previous studies that the NLRP3 inflammasome contributes to the progression of diabetic cardiomyopathy (DCM), and that ICA exerts a protective effect in DCM. However, the mechanism by which ICA may attenuate DCM by inhibiting the NLRP3 inflammasome still needs to be elucidated. Methods: The effects of ICA on the cardiac function and pathology of db/db mice were investigated. Levels of mitochondrial reactive oxygen species (mtROS), mitochondrial DNA (mtDNA), the NLRP3 inflammasome and pyroptosis were monitored in the hearts of DCM mice or H9c2 cardiomyoblasts induced by hyperglycaemia following ICA treatment. Furthermore, sirtuin 3 (SIRT3) activity and expression, as well as mitochondrial transcription factor A (TFAM) acetylation, were detected following ICA treatment. Results: We found that db/db mice treated with ICA exhibited significantly reduced cardiac hypertrophy and fibrosis, as well as improved cardiac function. ICA was associated with reduced mtROS, cytosolic mtDNA, NLRP3 inflammasome activation, and pyroptosis in the hearts of DCM mice or hyperglycaemia-induced H9c2 cardiomyoblasts, which may occur in a SIRT3-dependent manner. Ultimately, ICA-induced SIRT3 activation was associated with the deacetylation of TFAM. Discussion: These results suggested that ICA may attenuate DCM by inhibiting the NLRP3 inflammasome through a potential SIRT3-associated TFAM deacetylation pathway.