Effects of Secretome from Fat Tissues on Ion Currents of Cardiomyocyte Modulated by Sodium-Glucose Transporter 2 Inhibitor

Jhuo, Shih-Jie; Liu, I-Hsin; Tsai, Wei–Chung; Chou, Te-Wu; Lin, Yi‐Hsiung; Wu, Bin–Nan; Lee, Kun-Tai; Lai, Wen‐Ter

doi:10.3390/molecules25163606

Cited by 18 publications

(21 citation statements)

References 32 publications

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“…These modifications of adipocytokines by SGLT2 inhibitors and sulfonylurea treatment have been elucidated in a previous study [ 25 ]. In our previous study, the ion currents of cardiomyocyte could be modulated by adipocytokines after EMPA treatment, which might provide a possible mechanism for the antiarrhythmic effect [ 10 ]. In the EMPA-REG study, EMPA also showed benefits for patients with heart failure treatment and for the prevention of sudden cardiac death [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have also shown that SGLT2 inhibitors do not prolong the QT interval on electrocardiography, alleviate atrial remodeling, and improve mitochondrial function in diabetic rats [ 8 , 9 ]. We previously demonstrated that EMPA could modulate the effects of adipocytokines from fat tissues on the ion currents of cardiomyocytes and reduce arrhythmogenesis [ 10 ]. The effects of SGLT2 inhibitors, especially EMPA, on ventricular electrophysiological substrates have not been elucidated completely.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Jhuo

Liu

Tasi

et al. 2021

IJMS

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Empagliflozin (EMPA) is a sodium–glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Jhuo

Liu

Tasi

et al. 2021

IJMS

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“…mRNA collagen type III was increased in diabetic mouse atria, likely contributing to the interstitial atrial fibrosis observed in diabetic mice 77 . A recent study demonstrated that EAT‐released proteins can downregulate the delayed rectifier K + outward currents and increase L‐type calcium channel currents 78 . In addition, other ex vivo studies have demonstrated the effects of the pericardial secretome on the activation time and conduction velocity of atrial cells 79 .…”

Section: Pathophysiological Mechanisms Of Af Related To Eatmentioning

confidence: 99%

Updates on epicardial adipose tissue mechanisms on atrial fibrillation

et al. 2021

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Summary Obesity is a well‐known risk factor for atrial fibrillation (AF). Local epi‐myocardial or intra‐myocardial adiposity caused by aging, obesity, or cardiovascular disease (CVD) is considered to be a better predictor of the risk of AF than general adiposity. Some of the described mechanisms suggest that epicardial adipose tissue (EAT) participates in structural remodeling owing to its endocrine activity or its infiltration between cardiomyocytes. Epicardial fat also wraps up the ganglionated plexi that reach the myocardium. Although the increment of volume/thickness and activity of EAT might modify autonomic activity, autonomic system dysfunction might also change the endocrine activity of epicardial fat in a feedback response. As a result, new preventive therapeutic strategies are focused on reducing adiposity and weight loss before AF ablation or inhibiting autonomic neurotransmitter secretion on fat pads during open‐heart surgery to reduce the recurrence or postoperative risk of AF. In this manuscript, we review some of the novel findings regarding the pathophysiology and associated risk factors of AF, with special emphasis on the role of EAT in the electrical, structural, and molecular mechanisms of AF initiation and maintenance. In addition, we have included a brief note provided on epicardial fat preclinical models that could be useful for identifying new therapeutic targets.

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“…In mice with metabolic syndrome, adipokines induced a decrease in the expression level of potassium channels and an increase in the expression levels of calcium channels. Empagliflozin pretreatment could attenuate this effect in mice with metabolic syndrome, potentially reducing the risk of arrhythmias due to a disturbed ion homeostasis [72]. For the other SGLT2 inhibitors canagliflozin and ertugliflozin, as well as for the combined SGLT1/SGLT2 inhibitor sotagliflozin, no data regarding antiarrhythmic effects have been published so far.…”

Section: Heart Failure and Diabetes: Ventricular Arrhythmiasmentioning

confidence: 99%

SGLT2 Inhibitors and Their Antiarrhythmic Properties

Kolesnik

Scherr

Rohrer

et al. 2022

IJMS

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are gaining ground as standard therapy for heart failure with a class-I recommendation in the recently updated heart failure guidelines from the European Society of Cardiology. Different gliflozins have shown impressive beneficial effects in patients with and without diabetes mellitus type 2, especially in reducing the rates for hospitalization for heart failure, yet little is known on their antiarrhythmic properties. Atrial and ventricular arrhythmias were reported by clinical outcome trials with SGLT2 inhibitors as adverse events, and SGLT2 inhibitors seemed to reduce the rate of arrhythmias compared to placebo treatment in those trials. Mechanistical links are mainly unrevealed, since hardly any experiments investigated their impact on arrhythmias. Prospective trials are currently ongoing, but no results have been published so far. Arrhythmias are common in the heart failure population, therefore the understanding of possible interactions with SGLT2 inhibitors is crucial. This review summarizes evidence from clinical data as well as the sparse experimental data of SGLT2 inhibitors and their effects on arrhythmias.

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Effects of Secretome from Fat Tissues on Ion Currents of Cardiomyocyte Modulated by Sodium-Glucose Transporter 2 Inhibitor

Cited by 18 publications

References 32 publications

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Updates on epicardial adipose tissue mechanisms on atrial fibrillation

SGLT2 Inhibitors and Their Antiarrhythmic Properties

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