Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-07
  • 2020-08
  • Acetylation is an important protein modification that negati

    2019-07-08

    Acetylation is an important protein modification that negatively regulates the activity of Akt [16]. It has been showed that the level of Akt acetylation inversely correlates with Akt phosphorylation and signaling induced by IGF-1 or insulin. SIRT1 deacetylates Akt to promote its binding to PIP3 and consequent Akt activation [20]. Here we found that cardiac-specific SIRT1 knockout increased the expression of Akt acetylation and blunted IPO-induced activation of Akt. Ad-SIRT1 but not Ad-mSIRT1 reduced Akt acetylation and restored HPO-induced activation of Akt. Moreover, Akt acetylation-defective mutant (K20R) exhibited increased phosphorylation of Akt and enhanced protective effects against H/R injury, while constitutive Akt acetylation mutant (K20Q) exhibited repressed phosphorylation of Akt and blunted protective effects against H/R injury. These results demonstrate that the reduction of SIRT1 in diabetic hearts causes the increase of Akt acetylation, which represses the activation of Akt signaling and blunts the protective effects of IPO. It should be noted that complex mechanisms are involved in the impaired Akt signaling in diabetic hearts. Increased expression of PTEN is a negative regulator of Akt signaling in diabetes. Inhibition of PTEN has been shown to restore IPO-mediated cardioprotection in diabetic hearts by improving the PI3K/Akt signaling pathway [41]. Interestingly, SIRT1 has been reported to decrease PTEN acetylation and inhibit the interaction between PTEN and its receptors in COS7 Fasudil [42]. It is speculated that the inhibitory effects of SIRT1 on PTEN may be involved in the restoration of IPO-mediated cardioprotection in diabetic hearts. Further study may be needed to clarify the interrelationship between SIRT1 and PTEN in this process. There are still some limitations in the present study. First, our animal experiments were exclusively performed in HFD-STZ-induced diabetic mice. Whether the research findings can be applied to other diabetic models such as db/db mice needs further investigation. Second, the conclusion that SIRT1 up-regulation restores IPO-mediated protective effects in diabetic hearts by modulating Akt signaling pathway was verified by using Akt inhibitor MK-2206 rather than genetic manipulation. Third, there are huge species specific differences in the cardioprotective signaling pathways afforded by IPO [35]. The Akt signaling plays an important role in IPO-mediated cardioprotection in rodents and humans [43,44], but has no role in pigs [45]. Thus, whether our research findings can be applied to humans and other species needs further investigation. Despite these limitations, we believe that this study has established a direct link between SIRT1 and impaired Akt signaling in diabetic hearts, which may provide some insight into the problem of blunted cardioprotective effects by IPO in diabetes.
    Conclusions
    List of abbreviations
    Conflict of interest
    Transparency document
    Introduction We reported previously that genetic deficiency of mast cells (MCs) in Kit-dependent Kit mice, or pharmacologic inhibition of MCs in wild-type (WT) mice with the MC inhibitors disodium chromoglycate (DSCG) and ketotifen, reduced high cholesterol (1.25%), Western diet-induced body weight gain, and glucose tolerance, and increased insulin sensitivity [1]. Several studies showed that these Kit mice not only lack MCs but also show higher numbers of circulating neutrophils and elevated splenic and bone marrow Gr-1hiCD11bhi mature granulocytes, Gr-1intCD11bint mitotic granulocyte progenitors, and MC progenitor cells with reciprocal decreases of B and T cells, compared with those from WT control mice [2,3]. Therefore, reduced obesity and diabetes in Kit mice may associate with alterations of these inflammatory cell contents rather than the lack of MCs. Consistent with this hypothesis, Gutierrez et al. recently used Kit-independent Cpa3 mice and their WT controls, and demonstrated similar levels of body weight gain, body adipose tissue content, and glucose tolerance when mice were fed a cholesterol-free, high-fat diet (HFD) [4]. The same study also used DSCG to block MC activation, and found no effect of DSCG on HFD-induced bodyweight gain [4]. Unlike the Kit mice, Cpa3 mice show complete deficiency of MCs and partial basophil ablation, yet these mice have normal numbers of splenic and bone marrow lymphocytes and myeloid cells [5,6]. Similar to the observations from the Cpa3 mice, Chmelar et al. used another line of Kit-independent, MC constitutive-deficient Mcpt5-Cre R-DTA mice, and found that MC deficiency did not affect body weight gain, glucose tolerance, and insulin sensitivity when mice were fed the same cholesterol-free HFD [7]. In addition to MC-deficiency, Mcpt5-Cre R-DTA mice have comparable numbers of adipose tissue macrophages and T cells with those from Mcpt5-Cre-negative R-DTA control mice [7]. Therefore, authors from these studies concluded that “Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance” and “No Role for Mast Cells in Obesity-Related Metabolic Dysregulation” [4,7].