Abstract 13483: Pathological Decline in Incretin Hormone Glucagon-like Peptide-1 Causes Cardiac Apoptosis and Dysfunction in Pressure-overloaded Heart Failure Through Cyclic AMP-dependent Mechanisms. -Distinct Role of Protein Kinase a and EPAC

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Morihiko Aoyama ◽  
Yasuko K Bando ◽  
Haruya Kawase ◽  
Akio Monji ◽  
Toko Mitsui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Left Ventricular ◽  
Ample Evidence ◽  
Incretin Hormone ◽  
Myocardial Apoptosis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Distinct Role

Introduction: Ample evidence demonstrates cardiovascular protection by incretin hormone glucagon-like peptide-1 (GLP-1) through the cyclic AMP axis. GLP-1 is known for its inotropic effect on heart, however, the role of GLP-1 in heart failure remains uncertain. Hypothesis: To explore the pathophysiological role of GLP-1 in heart failure Methods: Pressure overload-induced heart failure model was generated by transverse aortic constriction in mice (TAC). Results: At 4 week after the operation, TAC exhibited systolic left-ventricular dysfunction, myocardial hypertrophy and augmented apoptosis. Unexpectedly, circulating GLP-1 concentration was markedly decreased in TAC (in pM; 0.86±0.10 for TAC versus 2.13±0.54 for sham) with concomitant reduction of myocardial cyclic AMP concentration (in pmole/mg protein; 33.0±1.4 for TAC versus 42.2±1.5). TAC exhibited pathological changes in signaling molecules of myocardial contractility [SERCA, phospho-phospholamban(Serine16; pPL), β-myosin heavy chain (MYH7)], remodeling (Akt/mTOR/S6K), and cell death markers (procaspase-3/Bcl2 for apoptosis and PINK/PARKIN complex for mitophagy detecting damaged mitochondria). All of these changes observed in TAC heart were reversed selectively by treatment with GLP-1 analog exendin-4 (Ex4; 24nmole/kg/day for 4 weeks) and indirect supplement of GLP-1 by a DPP4 inhibitor alogliptin (ALO; 10mg/kg/day for 4 weeks). In vitro TUNEL assay using cultured cardiomyocytes revealed that Ex-4 reduced myocardial apoptosis in a cAMP/EPAC1-dependent but PKA-independent manner (Figure). Conclusions: Pressure-overloaded heart failure exhibits decline in GLP-1, leading to cAMP/EPAC1-dependent impairment in myocardial apoptosis, and cAMP/PKA/pPL/SERCA-dependent myocardial contractile dysfunction. Our data suggest the distinct role of PKA and EPAC in pathophysiology underlying heart failure.

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling

2019 ◽  
Vol 115 (13) ◽  
pp. 1873-1885 ◽  
Author(s):  
Genki Naruse ◽  
Hiromitsu Kanamori ◽  
Akihiro Yoshida ◽  
Shingo Minatoguchi ◽  
Tomonori Kawaguchi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Mitochondrial Dynamics ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Atp Content ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

Abstract Aims Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production. Methods and results Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out. Conclusions Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

2012 ◽  
Vol 48 (2) ◽  
pp. 151-158 ◽  
Author(s):  
Hongjie Zhang ◽  
Jing Li ◽  
Xiangying Liang ◽  
Yun Luo ◽  
Ke Zen ◽  
...  
Keyword(s):  
Cell Model ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Mrna Levels ◽  
Incretin Hormone ◽  
Mucosal Layer ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Deficient Mice

It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7–36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

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