Cell death‐inducing DFFA‐like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation

Cell death-inducing DFFA-like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high-fat diet and a single injection of low-dose streptozotocin (27.5 mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP-activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin-resistant cardiac fibroblast (CF) model was induced by high glucose (15.5 mmol/L) and high insulin (104  μU/mL). We observed that insulin-resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co-localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.