Exogenous H₂S regulates endoplasmic reticulum-mitochondria cross-talk to inhibit apoptotic pathways in STZ-induced type I diabetes

Abstract

The upregulation of reactive oxygen species (ROS) is a primary cause of cardiomyocyte apoptosis in diabetes cardiomyopathy (DCM). Mitofusin-2 (Mfn-2) is a key protein that bridges the mitochondria and endoplasmic reticulum (ER). Hydrogen sulfide (HS)-mediated cardioprotection is related to antioxidant effects. The present study demonstrated that HS inhibited the interaction between the ER and mitochondrial apoptotic pathway. This study investigated cardiac function, ultrastructural changes in the ER and mitochondria, apoptotic rate using TUNEL, and the expression of ER stress-associated proteins and mitochondrial apoptotic proteins in cardiac tissues in STZ-induced type I diabetic rats treated with or without NaHS (donor of HS). Mitochondria of cardiac tissues were isolated, and MPTP opening and cytochrome (cyt C) and Mfn-2 expression were also detected. Our data showed that hyperglycemia decreased the cardiac function by ultrasound cardiogram, and the administration of exogenous HS ameliorated these changes. We demonstrated that the expression of ER stress sensors and apoptotic rates were elevated in cardiac tissue of DCM and cultured H9C2 cells, but the expression of these proteins was reduced following exogenous HS treatment. The expression of mitochondrial apoptotic proteins, cyt C, and mPTP opening was decreased following treatment with exogenous HS. In our experiment, the expression and immunofluorescence of Mfn-2 were both decreased after transfection with Mfn-2-siRNA. Hyperglycemia stimulated ER interactions and mitochondrial apoptotic pathways, which were inhibited by exogenous HS treatment through the regulation of Mfn-2 expression.

Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway

“…It is reported that DCM can cause the decrease expression of mitochondrial fusion protein and gap junction protein, 13, 14 although the mechanisms underlying these effects are not established. In addition, whether the activation of the gp78-ubiquitin proteasome system is involved in DCM is not clear.…”

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

“…There is ample evidence that cardiovascular disease is related to decreased expression of CSE [46, 47]. Our previous studies have found that H 2 S regulates the interactions and cause a switch among cell death pathways during hyperglycaemia [25, 32]. In the present study, we established a classic type I diabetic rat model to investigate the protective effects of H 2 S against hyperglycaemia-induced cardiac dysfunction.…”

“…Previous studies have shown that mitochondria are involved in the process of high glucose injury through enhancing the production of mitochondrial ROS and opening of the mPT pore [25]. The formation of ROS from cardiomyocytes is a key factor in the pathogenesis of diabetic complications [43, 48, 49].…”

“…In the NaHS treatment group, rats were given the intraperitoneal injection of NaHS (100 µM) with dosages based on a previous study [24] and our preliminary experiments [25]. Briefly, age-matched diabetic rats and control rats were sacrificed after treatment for 4 and 8 weeks.…”

Comparative Histological Study on the Effect of Stem Cells, and Gene Modified Stem Cells in Experimentally-Induced Diabetes Type 1 Cardiomyopathy

“…These findings denoted degeneration of cardiac muscle fibers. In support, these changes were recently attributed to upregulation of reactive oxygen species (ROS) [30] . Furthermore, another group [31] added and confirmed by proving that using a potent antioxidant as tiron could interfere with ROS pathway and hence prevents apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.…”