Empagliflozin ameliorates cardiac dysfunction in heart failure mice via regulating mitochondrial dynamics.

Empagliflozin has cardioprotective effects in patients with heart failure (HF). However, the mechanism by which empagliflozin protects against HF remains controversial. Study aimed to evaluate the effect of empagliflozin on myocardial fibrosis and cardiac function in HF mice and its possible mechanism. C57BL/6 mice were induced with HF by ligation of the left anterior descending coronary artery. At 4 weeks postoperation, mice were randomly given normal saline or empagliflozin for 8 weeks. Echocardiography was used to assess cardiac function. Masson's staining, immunohistochemistry and Western blot analysis were used to detect the degree of myocardial fibrosis. Changes in mitochondria were detected by observing mitochondrial morphology, measuring mitochondrial dynamics-related proteins and analysing the levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP). The mitochondrial fission inhibitor, mdivi1, was used to detect the relationship between mitochondrial dysfunction and cardiac dysfunction in HF mice. HF led to myocardial fibrosis and cardiac dysfunction. However, treatment with empagliflozin reduced these effects. Empagliflozin inhibited mitochondrial fission and improved energy metabolic efficiency in HF mice by regulating the expression of mitochondrial dynamics-related proteins. Similarly, mdivi1 attenuated mitochondrial dysfunction and cardiac dysfunction by inhibiting mitochondrial fission in HF mice. Regulation of mitochondrial dynamics, especially inhibition of mitochondrial fission, may be a potential target for reducing cardiac damage in patients with HF. Empagliflozin improved myocardial fibrosis and cardiac dysfunction by modulating mitochondrial dynamics in HF mice. Thus, the cardiac protective effect of empagliflozin may be related to the normalization of mitochondria and the increase in ATP production.

Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling

Diabetes is an independent risk factor for atrial fibrillation (AF). This study aimed to elucidate the pathophysiology of diabetes-related AF from the perspective of the gut microbial metabolite trimethylamine N-oxide (TMAO). In the present study, male rats received either a normal diet to serve as the control group or a high-fat diet/streptozotocin to induce type 2 diabetes mellitus. Then, diabetic rats were divided into two groups based on the presence or absence of 3,3-dimethyl-1-butanol (DMB, a specific TMAO inhibitor) in drinking water: the diabetic cardiomyopathy (DCM) group and the DCM + DMB group. Eight weeks later, compared with control rats, rats in the DCM group exhibited gut microbiota dysbiosis and systemic TMAO elevation. The inflammatory cytokines IL-1β, IL-6, and TNF-α were markedly increased in the atria of rats in the DCM group. Downregulated expression of connexin 40 and lateralized distribution of connexin 43 were also observed in the atria of DCM rats. AF inducibility was significantly higher in DCM rats than in control rats. Furthermore, DMB treatment effectively ameliorated atrial inflammation and connexin remodeling while markedly reducing plasma TMAO levels. DMB treatment also decreased the vulnerability of diabetic rats to AF. In conclusion, TMAO might promote atrial inflammation and connexin remodeling in the development of diabetes, which may play a key role in mediating diabetes-related AF. (AU)

Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling.

Diabetes is an independent risk factor for atrial fibrillation (AF). This study aimed to elucidate the pathophysiology of diabetes-related AF from the perspective of the gut microbial metabolite trimethylamine N-oxide (TMAO). In the present study, male rats received either a normal diet to serve as the control group or a high-fat diet/streptozotocin to induce type 2 diabetes mellitus. Then, diabetic rats were divided into two groups based on the presence or absence of 3,3-dimethyl-1-butanol (DMB, a specific TMAO inhibitor) in drinking water: the diabetic cardiomyopathy (DCM) group and the DCM + DMB group. Eight weeks later, compared with control rats, rats in the DCM group exhibited gut microbiota dysbiosis and systemic TMAO elevation. The inflammatory cytokines IL-1ß, IL-6, and TNF-α were markedly increased in the atria of rats in the DCM group. Downregulated expression of connexin 40 and lateralized distribution of connexin 43 were also observed in the atria of DCM rats. AF inducibility was significantly higher in DCM rats than in control rats. Furthermore, DMB treatment effectively ameliorated atrial inflammation and connexin remodeling while markedly reducing plasma TMAO levels. DMB treatment also decreased the vulnerability of diabetic rats to AF. In conclusion, TMAO might promote atrial inflammation and connexin remodeling in the development of diabetes, which may play a key role in mediating diabetes-related AF.