Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training
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 contr...
| Autores: | , , , , , |
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| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | Argentina |
| Recursos: | Universidad Nacional de La Plata |
| Repositorio: | SEDICI (UNLP) |
| Idioma: | inglés |
| OAI Identifier: | oai:sedici.unlp.edu.ar:10915/108322 |
| Acesso em linha: | http://sedici.unlp.edu.ar/handle/10915/108322 |
| Access Level: | acceso abierto |
| Palavra-chave: | Ciencias Médicas Ciencias Veterinarias IGF-1, nitric oxide synthase 1 CaMKII cardiac contractility exercise training |
| Resumo: | 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<sup>2+</sup> 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. |
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