P501GRK2 inhibition with small peptide improves cardiac function during heart failure

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Abstract

Heart Failure (HF) is a complex disease characterized by progressive cardiac dilation and loss of ATP content needed to accomplish myocardial contractile function. GRK2 is a serine/threonine kinase that phosphorylates and binds receptors coupled to G proteins, such as β-adrenergic receptors (βAR) and it is involved in the pathophysiology of HF since its increased levels are associated with the unfavorable development of such disease. Here we tested the therapeutic effects of a small peptide, whose has demonstrated the ability to inhibit GRK2 activity in vitro, on animal model of HF. For this study, 8 weeks old C57BL/6 mice were used and myocardial infarction (MI) of left ventricle was induced by means of a cryogen probe. Cardiac volume and function was assessed by Echocardiography pre- surgery and at 4, 6, 8 and 10 weeks post MI, followed by terminal hemodynamic evaluation by catheterization with Millar pressure transducer. Also, 6 weeks after MI, mice were implanted with a micro osmotic pump set to deliver 0.24 mg/day of grk2 inhibitor for 2 weeks. Finally, mice were sacrificed and heart samples collected for β binding, cAMP and ATP assays. MI induced a significant increase in left ventricle diastolic dimension (LVDD) and reduction of Ejection Fraction (EF) respect to control (LVDD: 4.27 ± 0.23 vs 3.7±0.09 mm, EF : 35.9 ± 0.02 vs 57 ± 3.4 %, MI vs control) at 6 week post surgery. At 8 weeks post MI, treated group showed a significant amelioration of cardiac function (EF: 51.7 ± 4 vs 30.81 ± 1.68, MI+pump vs MI) and attenuation of cardiac remodeling respect to MI control group (LVDD: 3.96 ± 0.11 vs 4.9 ± 0.1 mm , MI+pump vs MI).These results were still effective at 10 week post MI, while hemodynamic evaluation showed a significant amelioration in left ventricle diastolic pressure ( LVDp :1±2.5 vs 14.3 ± 1 mmHg in MI treated respect to MI Control group) and contractility after isoproterenol intravenous infusion (Δ to basal: 4544±320 vs+3197±205, MI+pump vs MI) indicating an improved emptying and a preserved contractile reserve of left ventricle induced by treatment. GRK2 inhibitor treatment restored βAR density (55±1.02 vs 40±1.43 fmol/mg, MI+pump vs MI) and cAMP production (15.9±0.53 vs 8.59±0.85 pmol/mg, MI+pump vs MI). Moreover, ATP content was increased in the heart samples from the treated group respect to post-MI HF not treated group (19450±3259 vs 11036±1896, Fluorescence intensity). These results demonstrate that a small peptide inhibitor of GRK2 is an effective therapeutic strategy to recover functional, biochemical and energetic cardiac properties during HF.

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