Exendin-4 inhibits structural remodeling and improves Ca 2+  homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway

Chen, Jing Jing; Wang, Dandan; Wang, Fangai; Shu, Shi; Chen, Yuting; Yang, Bo; Tang, Yanhong; Huang, Congxin

doi:10.1016/j.peptides.2017.02.008

Cited by 45 publications

(42 citation statements)

References 48 publications

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“…It is also considered that the activation of eNOS plays a protective role on blood vessels and may be damaged under I/R conditions (Brunner et al, 2003). Our present study shows that the level of phosphorylated eNOS decreased due to I/R injury but was significantly increased by exendin-4 administration, which was consistent with the previous studies of GLP-1 receptor agonists on other organs such as kidney and heart after I/R injury (Abdel-Latif, Heeba, Taye, & Khalifa, 2018;Baba et al, 2017;Chang et al, 2015;Chen et al, 2017).…”

Section: Discussionsupporting

confidence: 92%

Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

Zhai

et al. 2020

British J Pharmacology

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The aim of this study is to investigate the vasorelaxant effect of exendin-4, a GLP-1 receptor agonist on retinal capillaries under normal and ischaemia-reperfusion (I/R) conditions. Experimental Approach: Capillary diameters in the whole-mounted retina were directly observed using infrared differential interference contrast microscopy. A model of retinal I/R was established inraats,using high perfusion pressure in an anterior chamber. To assess the effects of exendin-4, it was administered through subcutaneous injection, intravitreal injection, or eye drops. The underlying mechanism was explored by immunofluorescence, qPCR, and capillary western blots.

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Section: Discussionsupporting

confidence: 92%

Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

Zhai

et al. 2020

British J Pharmacology

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“…Improvement of calcium handling in the HF model by exendin-4 may therefore maintain electrical activity homogeneity, which we showed in our previous study. 5) EXENDIN-4 AND ATRIAL ARRHYTHMOGENESIS Western blot analysis of phosphorylated RyR2 at S2814 and CaMK-II at T287 and total protein in sham, MI, MI + Ex-4, and MI + Ex-4 + Ex9-39 rat heart tissues. A, B: Western blot analysis of phosphorylated RyR2 at S2814 and total RyR2 protein level from the four groups of rat heart tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Indirect antiarrhythmic effects from improvement of ventricular remodeling: We have previously shown that exendin-4 improved adverse ventricular remodeling through increased ejection fraction, ameliorating ventricular and cardiomyocyte hypertrophy, and decreasing inter-stitial fibrosis. 5) These may indirectly reduce ventricular arrhythmias. 26,27) However, several lines of evidence from this study suggest that exendin-4 has a direct effect on ventricular arrhythmia generation by affecting electrophysiological characteristics, including ECG parameters, APD duration, the threshold of APD alternans, and SR calcium sparks-mediated calcium leak.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 Reduces Ventricular Arrhythmia Activity and Calcium Sparks-Mediated Sarcoplasmic Reticulum Ca Leak in Rats with Heart Failure

Chen

Zhou

et al. 2020

Int. Heart J.

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The aim of this study was to investigate the effect of exendin-4 (Ex-4) on ventricular arrhythmias and calcium sparks-mediated calcium leak in a myocardial infarction-heart failure model. We studied the influence of exendin-4 on ventricular arrhythmogenesis in a rat myocardial infarction-heart failure model. In vivo arrhythmia studies (electrocardiogram [ECG] telemetry studies), ex vivo arrhythmia studies calcium sparks tests, and analysis of total and phosphorylated ryanodine receptor (RyR) 2 and CaMK-II were carried out in sham group, myocardial infarction (MI) group, MI + Ex-4 and MI + Ex-4 + Exendin9-39 (Ex9-39) groups. ECG telemetry studies showed an antiarrhythmic effect of exendin-4 with reduction of spontaneous ventricular arrhythmias. Exendin-4 abbreviated the APD90, which was longer in the heart failure model, and increase the APD alternans thresholds. Exendin-4 also reduced the susceptibility to burst pacing-induced arrhythmia ex vivo. Subcellular sarcoplasmic reticulum (SR) calcium leak characteristics were tested in four groups of rat cardiomyocytes. Exendin-4 reduced calcium spark mass, spark frequency, and calcium leak, which may be due to reduced S2814-RyR2 and CaMK-II phosphorylation. Co-administration of exendin 9-39 with exendin-4 partly abolished the above-mentioned effect of exendin-4. These findings suggest that exendin-4 exerts an antiarrhythmic effect through decreasing SR calcium leak in spontaneous and burst pacing-induced ventricular arrhythmias, which may be due to reduced RyR2 phosphorylation and suppressed CaMK-II activity. Exendin-4 may act as a novel antiarrhythmic strategy in heart failure.

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“…17,19) The Sham and MI groups were administered the same volume of placebo (DMSO). Echocardiographic assessment: In order to evaluate left ventricular (LV) function and left atrial diameter (LAD) in four weeks after MI, transthoracic echocardiography was performed according to previously described procedures, 21) including following parameters: left ventricular enddiastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), LAD. All analyses were performed by a single investigator who was blinded to the three groups.…”

Section: Rat Model Of MImentioning

confidence: 99%

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

Liu

Shen

et al. 2019

Int. Heart J.

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Atrial inflammation and fibrosis are the critical processes involved in atrial fibrillation (AF) after myocardial infarction (MI). Fisetin is a dietary flavonoid that has shown forceful anti-inflammatory and antiproliferative properties in diverse models of disease. However, fisetin's role in atrial inflammation, fibrosis, and AF vulnerability post-MI remains completely unknown. Rats were subjected to MI surgery, by left anterior descending coronary artery ligation or sham operation, and treated with DMSO or fisetin via intraperitoneal injection. After 28 days, echocardiographic parameters were performed, and AF inducibility was tested. We further evaluated the inflammation, fibrosis of left atria (LA), and related signal pathways by RT-PCR, Western blot, and staining analysis. Compared to the MI group, fisetin treatment improved cardiac function, inhibited macrophage recruitment into the LA and production of IL-1β and TNF-α, and attenuated adverse atrial fibrosis following acute myocardial infarction (AMI). Electrophysiological recordings, using an isolated perfused heart, showed that MI-induced higher inducibility of AF and prolonged AF duration, interatrial conduction time (IACT), atrial effective refractory period (AERP) were significantly alleviated by fisetin. Mechanistically, fisetin markedly increased phosphorylated AMPK (p-AMPK) levels and suppressed NF-κB p65, p38MAPK, and smad3 phosphorylation in the LA post-MI. We demonstrate that fisetin improves LA expansion, cardiac function, atrial inflammation, fibrosis, and vulnerability to AF following MI by possibly regulating AMPK/NF-κB p65 and p38MAPK/smad3 signaling pathways.

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Exendin-4 inhibits structural remodeling and improves Ca 2+ homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway

Cited by 45 publications

References 48 publications

Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

Exendin-4 Reduces Ventricular Arrhythmia Activity and Calcium Sparks-Mediated Sarcoplasmic Reticulum Ca Leak in Rats with Heart Failure

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

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