Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Abstract

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway.

Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin‐Induced Diabetic ApoE−/− Mice

“…These indicated that interstitial collagen deposition, ERS-related apoptosis, and NF- κ B-mediated inflammation were induced in diabetic ApoE −/− mice. Consistent with the results of previous studies [ 15 , 16 , 19 , 24 ], atorvastatin treatment improved the histological abnormalities, fibrosis, and apoptosis of cardiomyocytes via inhibition of NF- κ B-induced inflammation and cleaved caspase-3-mediated apoptosis in the diabetic heart. To our knowledge, the present study is the first study to show that traditional Chinese medicine, GBE, could protect against diabetic myocardial injury, particularly apoptosis, myocardial fibrosis, and NF- κ B-mediated inflammation via inhibition of ERS-related apoptosis, as evidenced by the decrease in p-JNK, caspase-12, and cleaved caspase-3 expression.…”

“…Mice exhibiting plasma glucose levels > 12 mmol/L were considered diabetic and were used in the study ( n = 58) [ 13 , 14 ]. The diabetic mice were then treated with atorvastatin [ 15 , 16 ] (10 mg/kg/day, intragastric (i.g. ), n = 14), GBE at a low dose (200 mg/kg/day, i.g., n = 16), or GBE at a high dose (400 mg/kg/day, i.g., n = 17).…”

Andrographolide Ameliorates Diabetic Cardiomyopathy in Mice by Blockage of Oxidative Damage and NF‐κB‐Mediated Inflammation

“…Thomas et al [ 31 ] demonstrated that cardiomyocyte-specific NF- κ B signaling inhibition could attenuate diabetes-induced cardiac dysfunction through the suppression of the cardiac renin-angiotensin system. Interestingly, several anti-inflammatory compounds, such as atorvastatin [ 32 , 33 ] and cannabidiol [ 13 ], were found to be beneficial for the treatment of DCM. Consistent with previous studies [ 15 , 22 ], our results indicated that Andro treatment effectively suppressed NF- κ B activation and the expression of inflammatory cytokines, along with the subsequent decreased myocardial damage in diabetes.…”

Metoprolol and bisoprolol ameliorate hypertrophy of neonatal rat cardiomyocytes induced by high glucose via the PKC/NF‑κB/c‑fos signaling pathway

“…NF-κB is a key transcription factor regulating inflammatory responses and the expression of hyperglycemic stress related immediate early genes (35). Previous studies showed that NF-κB regulated several signal transduction pathways in cardiomyocytes under stimulation with HG (36,37). Hence, blocking NF-κB might attenuate HG-induced cardiac hypertrophy (38) in cardiac hypertrophy models.…”