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Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model.

ABSTRACT: Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10?ml solution of 5 × 106 IGF-1 loaded microspheres (MSPs) (n?=?8, IGF-1 MSPs), 5 × 106 unloaded MSPs (n?=?9; MSPs) or saline (n?=?7; CON) was performed 48?hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 106 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.

SUBMITTER: Baez-Diaz C

PROVIDER: S-EPMC7188803 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model.

Báez-Díaz Claudia C Blanco-Blázquez Virginia V Sánchez-Margallo Francisco-Miguel FM Bayes-Genis Antoni A González Irene I Abad Ana A Steendam Rob R Franssen Okke O Palacios Itziar I Sánchez Belén B Gálvez-Montón Carolina C Crisóstomo Verónica V

Scientific reports 20200428 1

Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 10<sup>6</sup> IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 10<sup>6</sup> unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 h ...[more]

PMID: 32346015

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Project description:BACKGROUND:In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS:Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS:Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0?±?2.3% vs 30.7?±?1.7% in vehicle-treated MI heart, p?<?0.05) and limited adverse remodelling (LV mass: 129?±?7 vs 176?±?14 mg in vehicle-treated MI hearts, p?<?0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661?±?192 vs 924?±?165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p?<?0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3? pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374?±?27 vs 183?±?41 µmol g protein-1 in vehicle-treated MI hearts, p?<?0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ?-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS:mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.

Dataset Information

Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model.

Publications

Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model.

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