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.

Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression.

This study aimed to investigate the effects of renal denervation (RDN) on diabetic cardiomyopathy (DCM) and explore the related mechanisms. Male Sprague-Dawley rats were fed high-fat chow and injected with low-dose streptozotocin to establish a DCM model. Six rats served as controls. The surviving rats were divided into three groups: control group, DCM group and DCM + RDN group. RDN surgery was performed in the fifth week. At the end of the experiment, all rats were subjected to 18F-FDG PET/CT and metabolic cage studies. Cardiac function and structure were evaluated by echocardiography and histology. Myocardial substrate metabolism and mitochondrial function were assessed by multiple methods. In the 13th week, the DCM rats exhibited cardiac hypertrophy and interstitial fibrosis accompanied by diastolic dysfunction. RDN ameliorated DCM-induced cardiac dysfunction (E/A ratio: RDN 1.07 ± 0.18 vs. DCM 0.93 ± 0.12, P < 0.05; E/E' ratio: RDN 10.74 ± 2.48 vs. DCM 13.25 ± 1.99, P < 0.05) and pathological remodeling (collagen volume fraction: RDN 5.05 ± 2.05% vs. DCM 10.62 ± 2.68%, P < 0.05). Abnormal myocardial metabolism in DCM rats was characterized by suppressed glucose metabolism and elevated lipid metabolism. RDN increased myocardial glucose uptake and oxidation while reducing the absorption and utilization of fatty acids. Meanwhile, DCM decreased mitochondrial ATP content, depolarized the membrane potential and inhibited the activity of respiratory chain complexes, but RDN attenuated this mitochondrial damage (ATP: RDN 30.98 ± 7.33 µmol/gprot vs. DCM 22.89 ± 5.90 µmol/gprot, P < 0.05; complexes I, III and IV activity: RDN vs. DCM, P < 0.05). Furthermore, both SGLT2 inhibitor and the combination treatment produced similar effects as RDN alone. Thus, RDN prevented DCM-induced cardiac dysfunction and pathological remodeling, which is related to the improvement of metabolic disorders and mitochondrial dysfunction.

Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure.

AIMS: The present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms. METHODS: Male wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF. RESULTS: Eight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors. CONCLUSION: HF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

Renal Denervation Attenuates Neuroinflammation in the Brain by Regulating Gut-Brain Axis in Rats With Myocardial Infarction.

Aims: The development of neuroinflammation deteriorates the prognosis of myocardial infarction (MI). We aimed to investigate the effect of renal denervation (RDN) on post-MI neuroinflammation in rats and the related mechanisms. Methods and Results: Male adult Sprague-Dawley rats were subjected to sham or ligation of the left anterior descending coronary artery to induce MI. One week later, the MI rats received a sham or RDN procedure. Their cardiac functions were analyzed by echocardiography, and their intestinal structures, permeability, and inflammatory cytokines were tested. The intestinal microbiota were characterized by 16S rDNA sequencing. The degrees of neuroinflammation in the brains of rats were analyzed for microglia activation, inflammatory cytokines, and inflammation-related signal pathways. In comparison with the Control rats, the MI rats exhibited impaired cardiac functions, intestinal injury, increased intestinal barrier permeability, and microbial dysbiosis, accompanied by increased microglia activation and pro-inflammatory cytokine levels in the brain. A RDN procedure dramatically decreased the levels of renal and intestinal sympathetic nerve activity, improved cardiac functions, and mitigated the MI-related intestinal injury and neuroinflammation in the brain of MI rats. Interestingly, the RDN procedure mitigated the MI-increased intestinal barrier permeability and pro-inflammatory cytokines and plasma LPS as well as ameliorated the gut microbial dysbiosis in MI rats. The protective effect of RDN was not significantly affected by treatment with intestinal alkaline phosphatase but significantly reduced by L-phenylalanine treatment in MI rats. Conclusions: RDN attenuated the neuroinflammation in the brain of MI rats, associated with mitigating the MI-related intestinal injury.