GLUCAGON-LIKE PEPTIDE-1 RECEPTOR ACTIVATION REDUCES COMPENSATORY HYPERTROPHY AND LEFT VENTRICULAR REMODELING IN A PORCINE MODEL OF ISCHEMIA AND REPERFUSION

Background: Adverse cardiac remodeling after MI is associated with excessive degradation of the extracellular matrix (ECM). IK-5001 is a low viscosity injectable solution that provides the polysaccharide alginate. After intracoronary injection into the MI area it undergoes phase transition forming a hydrogel which can support the ECM. We hypothesized that administration of alginate post-MI would provide a temporary scaffold and attenuate adverse LV remodeling. Methods: Acute MI was induced in 16 pigs by balloon occlusion of the proximal LAD for 2 hours. Animals randomly received intracoronary alginate or saline 4 days post-MI. LV function and remodeling were evaluated with cardiac MRI, 3D-echo and pressure-volume loops at 1 and 2 months post-MI. Histology and Western blot analysis were performed after 2 months. Results: Both groups had similar LVEF and infarct size 4 days post-MI. Coronary angiography immediately after alginate injection showed no impairment in coronary flow. However, 2 months post-MI, alginate-treated pigs exhibited reduced LV remodeling compared with controls demonstrated by reduced LV end-systolic volume, LV mass and sphericity (Table). Alginate-treated pigs had less cardiomyocyte hypertrophy and decreased interstitial fibrosis. Consistent with this, chronic activation of Akt and ERK was reduced. Alginate pigs also showed lower plasma levels of BNP and aldosterone. Interestingly, after 2 months, alginate pigs showed better systolic LV function: higher LVEF, better contractile reserve with dobutamine, and higher dP/dt. Conclusions: Intracoronary administration of alginate ameliorates adverse post-MI LV remodeling at the anatomical, histological and molecular level, and mitigates neurohormonal activation in a porcine model of MI. Alginate also improves systolic LV function. Intracoronary injection of alginate represents an exciting novel treatment option to reduce post-MI remodeling that merits assessment in clinical studies.

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Abstract 146: Glucagon-like Peptide-1 Receptor Activation Promotes Dual Benefits For Reversing Microvasculopathy And Mitochondrial Damage In Diabetic Heart.

Circulation Research ◽

10.1161/res.113.suppl_1.a146 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Akio Monji ◽

Yasuko K Bando ◽

Toko Mitsui ◽

Morihiko Aoyama ◽

Hiroya Kawase ◽

...

Keyword(s):

Oxidative Stress ◽

Receptor Activation ◽

Left Ventricular ◽

Mitochondrial Damage ◽

Wall Thickening ◽

Mouse Heart ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Impact

PURPOSE: Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) is a remedy for type 2 diabetes mellitus (T2DM). Ex4 ameliorates cardiac dysfunction in preclinical and clinical settings. However, it remains unclear whether the impact of Ex4 on cardiac remodeling in diabetic cardiomyopathy (DMC), of which primary characteristics are microvasculopathy and mitochondrial damage. Methods and Results: Diet-induced T2DM (DIO) mice and age- and gender-matched lean control mice were allocated into EX4 (24 nmole/kg/day for 40 days; DIO-Ex4 and LEAN-Ex4) and vehicle groups (DIO-veh and LEAN-veh). We first confirmed the GLP-1R expression in every single chamber of mouse heart by immunoblotting and PCR. Ex4 treatment ameliorated both systemic and cardiac insulin resistance without affecting body weight in DIO. Cardiac capillary density of DIO-veh was reduced compared to those LEAN-veh, which were reversed by Ex4 treatment. Tube formation assay and immunoblot analysis using culture endothelial cells revealed that Ex4 directly enhanced in vitro angiogenesis in a PKA/eNOS-dependent fashion. Systolic and diastolic left-ventricular (LV) dysfunctions observed in DIO-veh were restored by Ex4 with decline in LV wall thickening. Myocardial fibrosis detected using sirius-red staining and tissue oxidative stress detected by a fluorescence indicator DHE were attenuated in DIO-Ex4. Of note, analyses using transmission electron microscopy and a fluorescence indicator for damaged mitochondria (mitotracker red) revealed that Ex4 treatment reversed cardiac mitochondrial remodeling and increased healthy mitochondria. Ex4 treatment modulated cardiac oxidative stress balance by upregulating antioxidative molecules (SOD, thioredoxin, glutathione peroxidase) and reduction of NOX4 level; whereas it had no influence on NOX2 level. Conclusions: Ex4 enhances cardiac angiogenesis via GLP-1R-mediated activation of PKA/eNOS axis and accelerates reverses remodeling of myocardial mitochondria, at least in part, via its facilitating effects on antioxidative defense.

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Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion

Circulation ◽

10.1161/circulationaha.115.012427 ◽

2016 ◽

Vol 133 (10) ◽

pp. 954-966 ◽

Cited By ~ 101

Author(s):

Carlos G. Santos-Gallego ◽

Torsten P. Vahl ◽

Georg Goliasch ◽

Belen Picatoste ◽

Teresa Arias ◽

...

Keyword(s):

Receptor Agonist ◽

Porcine Model ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Myocardial Salvage ◽

Sphingosine 1 Phosphate

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The effect of long-term amiodarone administration on myocardial fibrosis and evolution of left ventricular remodeling in a porcine model of ischemic cardiomyopathy

SpringerPlus ◽

10.1186/s40064-016-3249-3 ◽

2016 ◽

Vol 5 (1) ◽

Cited By ~ 4

Author(s):

Anastasia Zagorianou ◽

Meletios Marougkas ◽

Stavros G. Drakos ◽

Nikolaos Diakos ◽

Panagiotis Konstantopoulos ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Ischemic Cardiomyopathy ◽

Porcine Model ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular

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Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22168711 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8711

Author(s):

Juliana de Freitas Germano ◽

Ankush Sharma ◽

Miroslava Stastna ◽

Chengqun Huang ◽

Marianne Aniag ◽

...

Keyword(s):

Ventricular Remodeling ◽

Heart Function ◽

Left Ventricular Remodeling ◽

In Silico Analysis ◽

Left Ventricular ◽

Mouse Heart ◽

Cardiac Events ◽

Short Acting ◽

Glucagon Like Peptide 1

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein–protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

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