| First Author | Burgos JI | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 112 |
| Pages | 16-26 | PubMed ID | 28867536 |
| Mgi Jnum | J:254369 | Mgi Id | MGI:6102754 |
| Doi | 10.1016/j.yjmcc.2017.08.014 | Citation | Burgos JI, et al. (2017) Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training. J Mol Cell Cardiol 112:16-26 |
| abstractText | Cardiac 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 cardiac contractility 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 CaMKII activation was downstream NO. In addition, we determined CaMKII activity (P-CaMKII) and phosphorylation of its target, Thr17-PLN. IGF-1, by a NO-dependent mechanism, significantly increased both (227.2+/-29.4% and 145.3+/-5.4%, respectively) while no changes in the CaMKII phosphorylation site of ryanodine receptor were evident. The improvement in contractility induced by IGF-1 was associated with increased Ca(2+) transient amplitude, rate of decay and SR content. Interestingly, this response was absent in cardiomyocytes from transgenic mice that express a CaMKII inhibitory peptide (AC3-I strain). Moreover, AC3-I mice subjected to swim training 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 in contractility induced by IGF-1 and exercise training. Interestingly, this pathway would not contribute to the adaptive hypertrophy. |
