The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Abstract

AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Cα. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis.

Role of the mTOR Signalling Pathway in Human Sepsis-Induced Myocardial Dysfunction

“…that PS6K and LC3B concentrations are negatively correlated, whereas PS6K and BIM concentrations are positively correlated support this hypothesis. In addition, our results are also consistent with the study by Zhang et al 19 However, our findings in patients differ from our previous basic research using a rat model of sepsis, which showed lower mTOR expression in the cardiomyocytes of rats with SIMD. It is possible that the differences are due to examining different stages of sepsis, when the myocardium has specific energy states or when mTOR pathway-associated effector levels in serum differ from those in tissue.…”

The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy

“…(Figure 7) The protective effects of autophagy in LPS-induced septic organ dysfunction have also been reported in previous studies (60,61). In particular, preservation of mitochondrial function and activation of autophagy may be a potential therapeutic opportunity for septic myocardial injury (11,12,62,63). Interestingly, melatonin has been reported as an autophagy regulator (36,37).…”

“…Activation of AMPK-mediated autophagy flux is found to protect against septic liver and kidney injury (67,68). In particular, during septic myocardial dysfunction, AMPK activation promotes autophagy, which protects against LPS-induced cardiotoxicity (59,63). In our study, we found that AMPK activation and phosphorylation significantly attenuated mitochondrial damage and myocardial dysfunction by decreasing pmTOR and p62 expressions and activating autophagy (Figures 2-3), which could be inhibited by Compound C (Figures 4-6).…”

Retracted: Bilobalide alleviates tumor necrosis factor‐alpha‐induced pancreatic beta‐cell MIN6 apoptosis and dysfunction through upregulation of miR‐153

“…Furthermore, AMPK/mTOR pathway played a crucial part in dysfunction according to previous reports. AMPK/mTOR pathway attenuated endotoxemia cardiac dysfunction by regulating autophagy in vivo; lipopolysaccharide promoted notably cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes (Zhang et al, ). Keampferol was also investigated to have an influence in dysfunction and endoplasmic reticulum stress of pancreatic β‐cells via this signaling pathway.…”