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Attenuation of ROS/Chloride Efflux-Mediated NLRP3 Inflammasome Activation Contributes to Alleviation of Diabetic
Songhan Li1, Shuohui Dong1, Bowen Shi1
1Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250014, China.
Abstract:
Diabetic cardiomyopathy (DCM) can develop in diabetes mellitus and is a major cause of morbidity and mortality. Surgical bariatric surgery procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes and have benefits regarding systolic and diastolic myocardial function. The NLR family pyrin domain containing 3 (NLRP3) inflammasome appears to participate in the development of DCM. However, whether SG surgery affects myocardial NLRP3 inflammasome-related pyroptosis to improve cardiac function remains unclear. This study was aimed at investigating the effect of SG surgery on NLRP3-associated pyroptosis in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a metabolic benefit of SG, including a reduced body weight, food intake, and blood glucose levels and restored glucose tolerance and insulin sensitivity postoperatively. We observed a marked decline in glucose uptake in rats with DCM, and this was restored after SG. Also, SG alleviated the dysfunction of myocardial contraction and diastole, delayed the progression of DCM, and reduced the NLRP3 inflammasome-mediated myocardial pyroptosis in vivo. H9c2 cardiomyocytes showed membrane disruption and DNA damage under a high glucose stimulus, which suggested myocardial pyroptosis. Using a ROS scavenger or chloride channel blocker in vitro restored myocardial NLRP3-mediated pyroptosis. Furthermore, we found that chloride efflux acted downstream of ROS generation. In conclusion, SG may ameliorate or even reverse the progression of DCM. Our study provides evidence that the SG operation alleviates NLRP3 inflammasome dysregulation in DCM. Clearance of ROS overburden and suppression of chloride efflux due to SG might act as the proximal event before inhibition of NLRP3 inflammasome in the myocardium, thus contributing to morphological and functional alleviation of DCM.
Insights
Sleeve gastrectomy (SG) surgery improves cardiac function in diabetic cardiomyopathy (DCM) by reducing NLRP3 inflammasome-mediated pyroptosis. This metabolic surgery alleviates myocardial damage by clearing reactive oxygen species (ROS) and suppressing chloride efflux.
Area of Science:
- Cardiology
- Metabolic Surgery
- Molecular Biology
Background:
- Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus, leading to increased morbidity and mortality.
- The NLR family pyrin domain containing 3 (NLRP3) inflammasome is implicated in DCM pathogenesis.
- The impact of bariatric surgery, specifically sleeve gastrectomy (SG), on NLRP3 inflammasome-mediated pyroptosis in DCM remains largely unknown.
Purpose of the Study:
- To investigate the effects of SG surgery on NLRP3 inflammasome-associated pyroptosis in a rat model of DCM.
- To examine the cellular phenotypes and molecular mechanisms underlying SG's impact on high glucose-stimulated cardiomyocytes.
Main Methods:
- A rat model of DCM was established using a high-fat diet and streptozotocin.
- Sleeve gastrectomy (SG) was performed on the DCM rats.
- Metabolic parameters (body weight, food intake, glucose tolerance, insulin sensitivity) were assessed.
- Myocardial function, NLRP3 inflammasome activation, and pyroptosis were evaluated *in vivo*.
- H9c2 cardiomyocytes were stimulated with high glucose *in vitro* to study pyroptosis, reactive oxygen species (ROS), and chloride efflux.
Main Results:
- SG surgery led to significant metabolic improvements, including weight loss, reduced food intake, normalized blood glucose, and restored glucose tolerance and insulin sensitivity.
- SG alleviated myocardial dysfunction, delayed DCM progression, and reduced NLRP3 inflammasome-mediated pyroptosis *in vivo*.
- High glucose induced pyroptosis in H9c2 cardiomyocytes, characterized by membrane disruption and DNA damage.
- ROS scavenging or chloride channel blockade *in vitro* attenuated NLRP3-mediated pyroptosis, with chloride efflux identified as downstream of ROS generation.
Conclusions:
- Sleeve gastrectomy (SG) demonstrates potential to ameliorate or reverse diabetic cardiomyopathy (DCM) progression.
- SG surgery alleviates NLRP3 inflammasome dysregulation in DCM.
- The beneficial effects of SG on DCM may involve the clearance of ROS overburden and suppression of chloride efflux, preceding the inhibition of myocardial NLRP3 inflammasome.
