Insulin-Like Growth Factor-1 Exerts Ca 2+ -Dependent Positive Inotropic Effects in Failing Human Myocardium

Abstract

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 μmol/L) on isometric twitch force (37°C, 1 Hz), intracellular Ca 2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca 2+ content (rapid cooling contractures), L-type Ca 2+ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca 2+ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133±4% of baseline values at 0.1 μmol/L; P <0.05). The IGF-1 receptor antibody αIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca 2+ transients and SR Ca 2+ content. IGF-1 (0.1 μmol/L) increased L-type Ca 2+ current amplitude by 24±7% ( P <0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca 2+ channel blockade with diltiazem partially prevented (≈50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na + -H + exchange (HOE642), or reverse-mode Na + -Ca 2+ exchange (KB-R7943) reduced the response to IGF-1 by ≈60% to 70%. IGF-1 exerts Ca 2+ -dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca 2+ ] i with IGF-1 originates from both enhanced L-type Ca 2+ currents and enhanced Na + -H + exchange-dependent reverse-mode Na + -Ca 2+ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.