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

Chen, Jingjing; Xu, Shunen; Zhou, Wei; Wu, Lirong; Wang, Long; Wei, Li

doi:10.1536/ihj.19-327

Cited by 18 publications

(13 citation statements)

References 27 publications

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“…Direct acute perfusion of 100 ng/mL FGF-23 reduced systolic Ca 2+ release and increased the spontaneous diastolic Ca 2+ leak, increasing the incidence of arrhythmogenic Ca 2+ events (Navarro-García et al, 2019). This phenotype is frequently observed in failing cardiomyocytes (Ruiz-Hurtado et al, 2015;Alvarado et al, 2017;Chen et al, 2020), which might explain the relationship between FGF-23 levels and HF incidence described previously in this review. The events observed in cells are strongly influenced by Ca 2+ mishandling and could be induced by RyRs hyperactivity and a reduction in SERCA activity, both of which are responsible for reduced SR Ca 2+ load (Navarro-García et al, 2019).…”

Section: Fgf-23 Causes Cardiac Dysfunctionsupporting

confidence: 68%

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

et al. 2021

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Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

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Section: Fgf-23 Causes Cardiac Dysfunctionsupporting

confidence: 68%

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

et al. 2021

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“…This is of interest, as GLP1R agonists have been implicated in preserving proper cardiac remodelling and shown to be cardioprotective following insults such as myocardial infarcts or ischaemia. [83][84][85] Moreover, GLP1R has shown to be essential for HR control in mice, and thus, its severe down-regulation in tumour hosts in this study may be responsible in part for cardiac dysfunction. 86 Additionally, SCGB1A1, also known as uteroglobin, was reduced 70-fold in tumour-bearing mice and increased 44 678-fold in tumour mice receiving ACVR2B/Fc.…”

Section: Discussionmentioning

confidence: 66%

“…Similarly, GLP1R was reduced 51‐fold in the tumour‐bearing mice and increased 71‐fold in ACVR2B/Fc‐treated HCT116 hosts. This is of interest, as GLP1R agonists have been implicated in preserving proper cardiac remodelling and shown to be cardioprotective following insults such as myocardial infarcts or ischaemia 83–85 . Moreover, GLP1R has shown to be essential for HR control in mice, and thus, its severe down‐regulation in tumour hosts in this study may be responsible in part for cardiac dysfunction 86 .…”

Section: Discussionmentioning

confidence: 77%

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Huot

Narasimhan

et al. 2020

J cachexia sarcopenia muscle

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Background Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. Methods NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. Results mHCT116 hosts displayed losses in fat mass (À 79%, P < 0.0001), bone mass (À 39%, P < 0.05), and SKM mass (quadriceps: À 22%, P < 0.001), in line with reduced muscle cross-sectional area (À 24%, P < 0.01) and plantarflexion force (À 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: À 16%, P < 0.0001; fractional shortening %: À 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass (+ 238%, P < 0.001), bone mass (+ 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force (+ 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Conclusions Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.

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“…MI, myocardial infarction; Ex-4, exendin-4; Ex9-39, exendin9-39; GLP-1, glucagon-like peptide-1 receptor; p-, phosphorylated; t-, total. studies showed that exendin-4 has direct electrophysiological effect on electrocardiogram parameters including QRS, QT and QTc intervals and calcium handling in ventricular arrhythmias (9,20). However, limited information is available regarding the effects of exendin-4 on atrial electrophysiology in heart failure.…”

Section: Discussionmentioning

confidence: 99%

“…The cardioprotective effects of exendin-4 are well known and a previous study by the authors demonstrated the cardioprotective effects of exendin-4 on a rat model of chronic MI through the endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway ( 9 ). Our previous studies showed that exendin-4 has direct electrophysiological effect on electrocardiogram parameters including QRS, QT and QTc intervals and calcium handling in ventricular arrhythmias ( 9 , 20 ). However, limited information is available regarding the effects of exendin-4 on atrial electrophysiology in heart failure.…”

Section: Discussionmentioning

confidence: 99%

Exendin‑4 inhibits atrial arrhythmogenesis in a model of myocardial infarction‑induced heart failure via the GLP‑1 receptor signaling pathway

Chen

Wang

et al. 2020

Exp Ther Med

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Glucagon-like peptide-1 receptor (GLP-1 receptor) agonists are considered to exert cardioprotective effects in models of acute and chronic heart disease. The present study aimed to investigate the role of exendin-4 (a GLP-1 receptor agonist) in atrial arrhythmogenesis in a model of myocardial infarction (MI)-induced heart failure and to elucidate the mechanisms underlying its effects. For this purpose, male Sprague-Dawley rats underwent sham surgery or left anterior descending artery ligation prior to being treated with saline/exendin-4/exendin-4 plus exendin9-39 (an antagonist of GLP-1 receptor) for 4 weeks. The effects of exendin-4 on atrial electrophysiology, atrial fibrosis and PI3K/AKT signaling were assessed. Rats with MI exhibited depressed left ventricular function, an enlarged left atrium volume, prolonged action potential duration, elevated atrial tachyarrhythmia inducibility, decreased conduction velocity and an increased total activation time, as well as total activation time dispersion and atrial fibrosis. However, these abnormalities were attenuated by treatment with the GLP-1 receptor agonist, exendin-4. Moreover, the expression levels of collagen I, collagen III, transforming growth factor-β1, phosphorylated PI3K and AKT levels in atrial tissues were upregulated in rats with MI. These changes were also attenuated by exendin-4. It was also found that these exedin-4-mediated attenutations were mitigated by the co-administration of exendin9-39 with exendin-4. Overall, the findings of the present study suggested that exendin-4 decreases susceptibility to atrial arrhythmogenesis, improves conduction properties and exerts antifibrotic effects via the GLP-1 receptor signaling pathway. These findings provide evidence for the potential use of GLP-1R in the treatment of atrial fibrillation.

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

Cited by 18 publications

References 27 publications

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Exendin‑4 inhibits atrial arrhythmogenesis in a model of myocardial infarction‑induced heart failure via the GLP‑1 receptor signaling pathway

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