Exogenous Hydrogen Sulfide Ameliorates Diabetic Myocardial Fibrosis by Inhibiting Cell Aging Through SIRT6/AMPK Autophagy

Abstract

Stress aging of myocardial cells participates in the mechanism of myocardial fibrosis (MF). Previous studies have shown that hydrogen sulfide (H 2 S) can improve MF, however the specific internal mechanism remains still unclear. Therefore, this study aims to explore whether H 2 S can improve myocardial cell aging induced by high glucose and myocardial fibrosis in diabetic rats by activating autophagy through SIRT6/AMPK. We observed that HG (high glucose, 33 mM) induced down-regulation of endogenous H 2 S-producing enzyme CSE protein expression, increased cell senescence, down-regulation of autophagy-related proteins Beclin1, Atg5, Atg12, Atg16L1, and inhibition of SIRT6/AMPK signaling pathway in H9c2 cardiomyocytes. H 2 S (NaHS: 400 μM) could up-regulate CSE protein expression, inhibit cell senescence, activate autophagy and SIRT6/AMPK signaling pathway. On the contrary, no above phenomena was achieved upon addition of CSE inhibitor PAG (dl-propargylglycine: mmol/L). In order to further elucidate the relationship between H 2 S and SIRT6/AMPK signaling pathway, dorsomorphin dihydrochloride (Dor), an inhibitor of AMPK signaling pathway, was added to observe the reversal of H 2 S’s inhibitory effect on myocardial cell aging. At the same, streptozotocin (STZ; 40 mg/kg) was injected intraperitoneally to build an animal model of diabetic SD rats. The results showed that myocardial collagen fibers were significantly deposited, myocardial tissue senescent cells were significantly increased and the expression of CSE protein was down-regulated, while SIRT6/AMPK signaling pathway and cell autophagy were significantly inhibited. H 2 S-treated (NaHS; 56 μmol/kg) could significantly reverse the above phenomenon. In conclusion, these findings suggest that exogenous H 2 S can inhibit myocardial cell senescence and improve diabetic myocardial fibrosis by activating CSE and autophagy through SIRT6/AMPK signaling pathway.

Exogenous Hydrogen Sulfide Plays an Important Role by Regulating Autophagy in Diabetic-Related Diseases

“…With the further research on the improvement of diabetes by H 2 S regulating autophagy, it may provide a new strategy for the treatment of diabetes. Diabetic cardiomyopathy Activating autophagy through activating AMPK/mTOR signaling pathway [59] Diabetes-induced myocardial fibrosis Inhibiting autophagy via activating PI3K/AKT1 signaling pathway [63] Diabetes-induced myocardial fibrosis Suppressing myocardial cell senescence via activating autophagy through activating SIRT6/AMPK signaling pathway [66] High glucose-induced endothelial cell dysfunction Inhibiting autophagy via the Nrf2/ROS/AMPK signaling pathway [75] Diabetes-induced renal fibrosis Activating autophagy via inhibiting TGFβ1/NF-κB/AKT pathways [83] Diabetic dysfunctional vascular smooth muscle Inhibiting autophagy via suppressing the AMPK/mTOR pathway [92] Diabetic depression Promoting autophagy via activating BDNF/TrkB pathway [99]…”

“…HG also aggravated diabetic myocardial fibrosis by increasing the expression levels of type III collagen, MMP-8, MMP-13 and MMP-14 in the diabetic myocardium and inhibited autophagy by downregulating the expression levels of autophagy-related proteins including Atg5, Atg16L1 and Beclin1 in HGinduced H9C2. Meanwhile, exogenous H 2 S could reverse the above changes, indicating that exogenous H 2 S could improve diabetic myocardial fibrosis, inhibit myocardial cell senescence and promote autophagy in diabetes models [66]. In addition, it has been reported that the upregulation of autophagy inhibited myocardial cell senescence [67].…”

“…AMPK and the AMPK-autophagy pathway were involved in senility [69]. Mechanism research showed that exogenous H 2 S activated the SIRT6/AMPK signaling pathway suppressed by HG through upregulating SIRT6 and AMPK protein expression, while the SIRT6 inhibitor or AMPK inhibitor reversed the effects of exogenous H 2 S on autophagy and senescence, suggesting that exogenous H 2 S could improve diabetic fibrosis by suppressing myocardial cell senescence via activating autophagy through activating the SIRT6/AMPK signaling pathway [66]. The reference needs to be studied by using an autophagy inhibitor to confirm the effects of autophagy on diabetic myocardial fibrosis.…”

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

“…In addition, a previous study reports that NaHS can effectively reduce CF by inhibiting the expression of Ang II-induced motilin, connective tissue growth factor and type I collagen, as well as the expression of heme oxygenase-1 in cardiac fibroblasts, a process associated with the reduction of the NOX4-ROS-ERK1/2 signal transduction axis [ 146 ]. Recent studies further reveal that treatment with NaHS can markedly improve CF in diabetic rats by promoting CSE synthesis and autophagy through stimulation of the SIRT-6/AMPK and PI3K/AKT/eNOS pathways [ 147 , 148 ]. Similarly, in a thyroxine-induced CF rat model, H 2 S induces a protective effect by regulating autophagy via activation of the PI3K/AKT pathway [ 149 ].…”

Polydatin Protects Against Articular Cartilage Degeneration by Regulating Autophagy Mediated by AMPK/Mtor Signaling Pathway

“…The inhibitor of AMPK was used to assess the mechanism of polydatin on the C28/I2 cells. The C28/I2 cells were divided into four groups: control (only DMEM/F-12), LPS (DMEM/F-12 contain 5 μg/mL LPS, incubate for 24 h), LPS+polydatin (DMEM/F-12 contain 5 μg/mL LPS and 1 μM polydatin, incubate for 24 h), and LPS+polydatin+Dorsomorphin 2HCl (After treated with 10 μM Dorsomorphin 2HCl for 1 h, C28/I2 cells were cultured in DMEM/F-12 with 5 μg/mL LPS and 1 μM polydatin for 24 h) [15]. Then, the role of Dorsomorphin 2HCl on the proliferation and apoptosis of C28/I2 cells and the mechanism were also detected according to the above description.…”