Does apelin mediate the cardioprotective effects of IGF-1?

YEVES AM; GODOY COTO J; CAVALLI F; PEREYRA EV; CALDIZ CI; ENNIS IL

Berlin

Congreso; XXIV World Congress. International Society for Heart Research; 2022

IntroductionHypertension is a significant health risk that affects millions of peopleworldwide. It has been well established that patients with hypertensivecardiac hypertrophy die most frequently because of heart failure.Hypertensive myocardium is associated to mitochondrial dysfunction andredox disbalance. On the other hand, exercise training produces severalbeneficial effects, usually mediated by humoral factors. In this sense, apelinand insulin like growth factor-1 (IGF-1) increase in response to exerciseexerting cardioprotective effects. Particularly, whether apelin mediates thecardioprotective effects of IGF-1 by an autocrine paracrine mechanism is notclear yet.ObjectiveTo determine the acute myocardial effects of apelin or IGF-1 on oxidativestress and mitochondrial status, as well as the possible crosstalk betweenthe signaling pathways triggered by both humoral factors.Methods3-month-old SHR isolated hearts or isolated cardiomyocytes wereperfused 10 min in presence or absence of apelin, IGF-1 and the specificantagonist of their receptors (AG1024 and ML221 for IGF1R and APJ,respectively). We mainly explored the effects on reactive oxygen species(ROS) production, antioxidant activity, mitochondrial function, and thecrosstalk between IGF-1 and apelin signaling.ResultsIGF-1 and apelin increased myocardial SOD activity (U/mg, IGF-1: 59.8 ±5.2, Apelin: 56 ± 3.9 vs Control: 41.6 ± 3) and decreased ROS production (%,IGF-1: 64.6 ± 8.6, Apelin: 59.6 ± 5.4 vs Control: 100 ± 8.3). Both agentsprevented DYloss induced by H2O2 (IGF-1: 0.917 ± 0.021, Apelin: 0.984 ±0.024 vs Control: 0.827 ± 0.024) and inhibited mPTP opening (CRC, IGF-1:289 ± 11, Apelin: 292 ± 23 vs Control: 142 ± 28). The antagonism of IGF1R(AG1024) or of APJ (ML221) cancelled all these beneficial effects.Exogenously administrated IGF-1 increased the mRNA cardiacexpression of APJ (IGF-1: 175.8 ± 27.7 vs Control: 100 ± 16), similarly tothe effect of swim training, were it is well known that an increase in IGF-1takes place (Apelin mRNA: trained: 121.7 ± 3.3 vs Sed: 100 ± 5.3; APJmRNA: trained: 211 ± 38.3 vs Sed 100 ± 3; APJ protein: trained: 159.26 ±8.8 vs Sed: 100 ± 9.57). Even more, the mitochondrial protective effectsinduced by IGF-1 were prevented by the pharmacological inhibition of APJ(IGF-1 + ML221, SOD activity: 43.28 ± 2.75, CRC: 57 ± 7).ConclusionOur preliminary data suggest that apelin/APJ may be an intermediatestep in the signaling cascade trigger by IGF-1 responsible forcardioprotection