Korean J Physiol Pharmacol.  2022 Nov;26(6):541-556. 10.4196/kjpp.2022.26.6.541.

Gaseous signal molecule SO₂ regulates autophagy through PI3K/ AKT pathway inhibits cardiomyocyte apoptosis and improves myocardial fibrosis in rats with type II diabetes

• Zhao J
• Wu Q
• Yang T
• Nie L
• Liu S
• Zhou J
• Chen J
• Jiang Z
• Xiao T
• Yang J
• Chu C

• KMID: 2534529
• DOI: http://doi.org/10.4196/kjpp.2022.26.6.541

Abstract

Myocardial fibrosis is a key link in the occurrence and development of diabetic cardiomyopathy. Its etiology is complex, and the effect of drugs is not good. Cardiomyocyte apoptosis is an important cause of myocardial fibrosis. The purpose of this study was to investigate the effect of gaseous signal molecule sulfur dioxide (SO₂ ) on diabetic myocardial fibrosis and its internal regulatory mechanism. Masson and TUNEL staining, Western-blot, transmission electron microscopy, RT-qPCR, immunofluorescence staining, and flow cytometry were used in the study, and the interstitial collagen deposition, autophagy, apoptosis, and changes in phosphatidylinositol 3-kinase (PI3K)/AKT pathways were evaluated from in vivo and in vitro experiments. The results showed that diabetic myocardial fibrosis was accompanied by cardiomyocyte apoptosis and down-regulation of endogenous SO₂ -producing enzyme aspartate aminotransferase (AAT)_1/2 . However, exogenous SO₂ donors could up-regulate AAT_1/2 , reduce apoptosis of cardiomyocytes induced by diabetic rats or high glucose, inhibit phosphorylation of PI3K/AKT protein, up-regulate autophagy, and reduce interstitial collagen deposition. In conclusion, the results of this study suggest that the gaseous signal molecule SO₂ can inhibit the PI3K/AKT pathway to promote cytoprotective autophagy and inhibit cardiomyocyte apoptosis to improve myocardial fibrosis in diabetic rats. The results of this study are expected to provide new targets and intervention strategies for the prevention and treatment of diabetic cardiomyopathy.

Keyword

Apoptosis; Autophagy; Myocardial fibrosis; PI3K/AKT pathway; Sulfur dioxide

Figure

• 

  Fig. 1 Animal grouping and drug treatment. Sprague–Dawley (SD) rats were administered with 8 weeks of different dietary interventions followed by intraperitoneal injection of streptozotocin (STZ) or citric acid-sodium citrate buffer, and the dietary treatment was continued for 8 weeks after the successful establishment of the diabetic rats model, meanwhile intraperitoneal injection of exogenous sulfur dioxide (SO2) donor (Na2SO3/NaHSO3) or equivalent saline for 8 weeks. DC, diabetic cardiomyopathy.

• 

  Fig. 2 Exogenous sulfur dioxide (SO2) can up-regulate the expression level of aspartate aminotransferase (AAT)1/2. (A, C) Western blot analysis of the expression changes of AAT1/2 in the myocardial tissue of type II diabetes rats. n = 3, *p < 0.05 vs. Control; #p < 0.05 vs. DC. (B, D) Western blot analysis of the expression changes of AAT1/2 in H9c2 cardiomyocytes; n = 3, *p < 0.05 vs. Control; #p < 0.05 vs. HG; $p < 0.05 vs. HG + SO2. Values are presented as mean ± SD. DC, diabetic cardiomyopathy; HG, high glucose.

• 

  Fig. 3 Sulfur dioxide (SO2) can reduce the formation of myocardial collagen fibers in type II diabetic rats. (A) Masson staining results of myocardial tissue of the rats in the Control, DC, DC + SO2, and SO2 groups. 10 × 40 magnification field of view (blue-stained part is collagen fibers, and black arrows are collagen fibers), n = 3; (B) Fraction of Masson-stained collagen volume, **p < 0.01 vs. Control; ##p < 0.01 vs. DC. (C, D) Western blot analysis of the protein expression changes of MMP3, MMP8, MMP13, and CollagenIII in the myocardial tissue of the rats in the respective group. n = 3, *p < 0.05 vs. Control; #p < 0.05 vs. DC. (E) RT-qPCR detection of the expression of Col3a1 in the myocardial tissue of the rats. n = 3, **p < 0.01 vs. Control; ##p < 0.01 vs. DC, Take GAPDH as reference. Values are presented as mean ± SD deviation. DC, diabetic cardiomyopathy.

• 

  Fig. 4 SO2 inhibits high-glucose-induced apoptosis in cardiac myocytes. (A) Flow cytometry to detect the apoptosis rate of H9c2 cardiomyocytes under high glucose environment (33 mM), Q2 + Q4 represents the incidence of apoptosis, n = 3; (B–F) The expression changes of apoptosis-associated proteins Bax, Bcl2, Caspase3, Cleaved-Caspase3, Caspase9, and Cleaved-Caspase9 in myocardial cells of each group were detected through Western blot. n = 3. Values are presented as mean ± SD. SO2, sulfur dioxide; HG, high glucose. *p < 0.05 vs. Control; #p < 0.05 vs. HG; $p < 0.01 vs. HG + SO2.

• 

  Fig. 5 SO2 reduces cardiomyocyte apoptosis in diabetic rats. (A) TUNEL staining of myocardial tissue of the rats in the Control, DC, DC + SO2 and SO2 groups (apoptosis-positive cells in TUNEL staining are in brown, and they are indicated by black arrows), n = 3. Images were acquired at 10 × 40 magnification; (B) Quantitative results of TUNEL-stained positive cells in the myocardial tissue of the rats in the respective group, **p < 0.01 vs. Control. ##p < 0.01 vs. DC; (C–G) Western blot detection of the expressions of Bax, Bcl2, Cleaved Caspase3, Caspase3, Cleaved Caspase9, Caspase9 in the myocardial tissue of the rats in the respective group. n = 3, *p < 0.05 vs. Control; #p < 0.05 vs. DC; (H, I) Detection of mRNA expression levels of Bax and Caspase3 in the myocardial tissue by RT-qPCR, **p < 0.01 vs. Control. ##p < 0.01 vs. DC, GAPDH is taken as the internal parameter. Values are presented as mean ± SD. SO2, sulfur dioxide; DC, diabetic cardiomyopathy.

• 

  Fig. 6 Sulfur dioxide (SO2) can up-regulate the level of autophagy in the myocardial tissue of type II diabetes rats. (A) The ultrastructure of cardiomyocytes and the changes of autophagosomes in type II diabetes rats were observed under transmission electron microscope. The arrows indicate autophagosomes, and the part indicated by the arrows in the upper figure is enlarged in the lower figure. The TEM figure was observed under ×5,000 at 2 µm bar. (B, C) Western blot analysis of the expression changes of autophagy-associated proteins (including LC3II/I, Beclin1, Atg5, Atg16L1 and P62) in the myocardial tissue of the rats in the respective group. n = 3, *p < 0.05 vs. Control. #p < 0.05 vs. DC. (D, E) Western blot analysis of the expression changes of LC3II/I, Beclin1, Atg16L1 and P62 of H9c2 cardiomyocytes in the Control, HG, HG + SO2, HG + SO2 + HDX and SO2 groups. n = 3; *p < 0.05 vs. Control. #p < 0.05 vs. HG. $p < 0.05 vs. HG + SO2. (F) Immunofluorescence observation of Beclin1 expression in H9c2 cardiomyocytes from each group (magnification; ×10). (G) RT-qPCR detection of P62 mRNA expression in rat myocardial tissue, *p < 0.05 vs. Control; #p < 0.01 vs. DC, take GAPDH as a reference. Values are presented as mean ± SD. DC, diabetic cardiomyopathy; HG, high glucose.

• 

  Fig. 7 Sulfur dioxide (SO2) can reverse the up-regulation of phosphatidylinositol 3-kinase (PI3K)/AKT expression induced by high glucose. (A, C) Western blot detection to observe the expression changes of P-PI3K, PI3K, P-AKT, AKT in the myocardial tissues of the rats in the Control, DC, DC + SO2, and SO2 groups. n=3; *p < 0.05 vs. Control; #p < 0.01 vs. DC. (B, D) Western blot detection was used to observe the protein expression changes of P-PI3K, PI3K, P-AKT, and AKT of H9c2 cardiomyocytes in the Control, HG, HG + SO2, HG + SO2 + 740 Y-P and SO2 group. n = 3; *p < 0.05 vs. Control. #p < 0.05 vs. HG. $p < 0.05 vs. HG + SO2. Values are presented as mean ± SD. DC, diabetic cardiomyopathy; HG, high glucose.

• 

  Fig. 8 Sulfur dioxide (SO2) antagonizes apoptosis of H9c2 cardiomyocytes by down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT and activating autophagy. (A, B) Western blot detection was used to observe the expression changes of autophagy-associated proteins (including LC3II/I, Beclin1, Atg16L1 and P62 of H9c2 cardiomyocytes) in the Control group, the HG group, the HG + SO2 group, the HG + SO2 + 740 Y-P group and the SO2 group. (C–G) Western blot detection was used to observe the expression changes of apoptosis-associated proteins Bax, Bcl2, Caspase3, Cleaved-Caspase3, Caspase9, and Cleaved-Caspase9 of H9c2 cardiomyocytes in the Control, HG, HG + SO2, HG + SO2 + 740 Y-P, and SO2 groups. n = 3. Values are presented as mean ± SD. DC, diabetic cardiomyopathy; HG, high glucose. *p < 0.05 vs. Control. #p < 0.05 vs. HG. $p < 0.05 vs. HG + SO2.

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