Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation.

Abstract

Sirtuin 3 (SIRT3) is a potential therapeutic target for cardiovascular, metabolic, and other aging-related diseases. In this study, we investigated the role of SIRT3 in diabetic cardiomyopathy (DCM). Mice were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes mellitus. Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice, as subsequently confirmed by real-time PCR and Western blotting. To explore the role of SIRT3 in DCM, SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ. We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction, increased lactate dehydrogenase (LDH) level in the serum, decreased adenosine triphosphate (ATP) level in the myocardium, exacerbated myocardial injury, and promoted myocardial reactive oxygen species (ROS) accumulation. Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA, then exposed to high glucose (HG, 25.5 mM). We found that downregulation of SIRT3 further increased LDH release, decreased ATP level, suppressed the mitochondrial membrane potential, and elevated oxidative stress in HG-treated cardiomyocytes. SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and cleaved caspase 3, and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3 (NLRP3), caspase 1 p20, and interleukin-1β both in vitro and in vivo. Collectively, SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage, increased ROS accumulation, promoted necroptosis, possibly activated the NLRP3 inflammasome, and ultimately exacerbated DCM in the mice. These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM.

• Authors: Shu Song, Yue Ding, Guo-Liang Dai, Yue Zhang, Meng-Ting Xu, Jie-Ru Shen, Ting-Ting Chen, Yun Chen, Guo-Liang Meng
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 2 Pg. 230-241 (Feb 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 32770173 (Publication Type: Journal Article)

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Sirt3 protein, mouse
• Streptozocin
• Sirtuin 3

Topics

• Animals
• Diabetes Mellitus, Experimental (complications, genetics)
• Diabetic Cardiomyopathies (genetics)
• Inflammasomes (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (pathology)
• Myocytes, Cardiac (pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Necroptosis (genetics)
• Oxidative Stress (genetics)
• Rats
• Rats, Sprague-Dawley
• Sirtuin 3 (genetics)
• Streptozocin