Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training

BURGOS, JI; YEVES AM; BARRENA JP; PORTIANSKI EL; VILA PETROFF MG; ENNIS IL

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2017 p. 16 - 26

0022-2828

A B S T R A C TCardiac adaptation to endurance training includes improved contractility by a non-yet clarified mechanism.Since IGF-1 is the main mediator of the physiological response to exercise, we explored its effect on cardiaccontractility and the putative involvement of nitric oxide (NO) and CaMKII in control and swim-trained mice.IGF-1 increased cardiomyocyte shortening (128.1 ± 4.6% vs. basal; p ˂ 0.05) and accelerated relaxation(time to 50% relengthening: 49.2 ± 2.0% vs. basal; p ˂ 0.05), effects abrogated by inhibition of: AKT with MK-2206, NO production with the NO synthase (NOS) inhibitor L-NAME and the specific NOS1 inhibitor nitroguanidine(NG), and CaMKII with KN-93. In agreement, an increase in NO in response to IGF-1(133.8 ± 2.2%) was detected and prevented by both L-NAME and NG but not KN-93, suggesting that CaMKIIactivation was downstream NO. In addition, we determined CaMKII activity (P-CaMKII) and phosphorylation ofits target, Thr17-PLN. IGF-1, by a NO-dependent mechanism, significantly increased both (227.2 ± 29.4% and145.3 ± 5.4%, respectively) while no changes in the CaMKII phosphorylation site of ryanodine receptor wereevident. The improvement in contractility induced by IGF-1 was associated with increased Ca2+ transientamplitude, rate of decay and SR content. Interestingly, this response was absent in cardiomyocytes fromtransgenic mice that express a CaMKII inhibitory peptide (AC3-I strain). Moreover, AC3-I mice subjected to swimtraining did develop physiological cardiac hypertrophy but not the contractile adaptation.Therefore, we conclude that NO-dependent CaMKII activation plays a critical role in the improvement incontractility induced by IGF-1 and exercise training. Interestingly, this pathway would not contribute to theadaptive hypertrophy.1. IntroductionExercise training is a consolidated approach to reduce cardiovascularrisk factors that in the last years has emerged as a promisingstrategy for the treatment of cardiovascular disease. Several reportshave demonstrated its ability not only to positively shift pathologiccardiac remodeling but also to recover abnormal Ca2+ handling andimprove contractility [1,2]. The first large prospective randomizedstudy to actually provide evidence for a training-induced improvementof ejection fraction and reduction of LV end-diastolic diameter in amixed population of subjects with ischemic and dilated cardiomyopathycame from Hambrecht et al. [3]. Later, these findings were corroboratedby the Exercise in Left Ventricular Dysfunction and ChronicHeart Failure study [4].Exercise training raises oxygen consumption, and as a consequencecardiac output and oxygen transport increase to match the metabolic