TY - JOUR
T1 - Insulin-like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity
AU - Roof, S. R.
AU - Boslett, J.
AU - Russell, D.
AU - del Rio, C.
AU - Alecusan, J.
AU - Zweier, J. L.
AU - Ziolo, M. T.
AU - Hamlin, R.
AU - Mohler, P. J.
AU - Curran, J.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Aims: Insulin-like growth factor 1 (IGF-1)-dependent signalling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo 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 in vivo model of chronic catecholamine-induced cardiomyopathy. Methods: Rats were perfused with isoproterenol via osmotic pump (1 mg kg-1 per day) and treated with 2 mg kg-1 IGF-1 (2 mg kg-1 per day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analysed for fibrosis and apoptosis, and relevant biochemical signalling cascades were assessed. Results: After 4 weeks, 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 p110α 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. Conclusion: IGF-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.
AB - Aims: Insulin-like growth factor 1 (IGF-1)-dependent signalling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo 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 in vivo model of chronic catecholamine-induced cardiomyopathy. Methods: Rats were perfused with isoproterenol via osmotic pump (1 mg kg-1 per day) and treated with 2 mg kg-1 IGF-1 (2 mg kg-1 per day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analysed for fibrosis and apoptosis, and relevant biochemical signalling cascades were assessed. Results: After 4 weeks, 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 p110α 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. Conclusion: IGF-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.
KW - Adrenergic stimulation
KW - Cardiomyopathy
KW - Diastolic dysfunction
KW - Insulin-like growth factor 1
KW - Systolic dysfunction
KW - Tetrahydrobiopterin
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U2 - 10.1111/apha.12607
DO - 10.1111/apha.12607
M3 - Article
C2 - 26399932
AN - SCOPUS:84959539161
SN - 0370-839X
VL - 216
SP - 421
EP - 434
JO - Acta Physiologica Scandinavica
JF - Acta Physiologica Scandinavica
IS - 4
ER -