Insulin-like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity

AimsInsulin-like growth factor 1 (IGF-1)-dependent signalling promotes exercise-induced physiological cardiac hypertrophy. However, the invivo therapeutic potential of IGF-1 for heart disease is not well established. Here, we test the potential therapeutic benefits of IGF-1 on cardiac function using an invivo model of chronic catecholamine-induced cardiomyopathy. MethodsRats were perfused with isoproterenol via osmotic pump (1mgkg(-1) per day) and treated with 2mgkg(-1) IGF-1 (2mgkg(-1) per day, 6days a week) for 2 or 4weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4weeks. Heart sections were analysed for fibrosis and apoptosis, and relevant biochemical signalling cascades were assessed. ResultsAfter 4weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax) and structural remodelling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110 signalling and activated Akt are selectively upregulated in Iso+IGF-1-treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups; however, tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. ConclusionIGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies.