Efeito do treinamento físico na cardiomiopatia induzida por hiperatividade simpática em camundongos com ablação dos receptores alpha 2A/alpha 2C- adrenérgicos / Effect of exercise training on cardiomyopathy induced by sympathetic hiperactivity in mice lacking a2A/a2C- adrenoceptors

AUTOR(ES)
DATA DE PUBLICAÇÃO

2006

RESUMO

Presynaptic a2-adrenoceptors (a2 AR) regulate the cardiovascular function by inhibiting neurotransmitter release on the sympathetic nerve terminals. We have recently reported that disruption for both a2A and a2C AR subtypes in mice (KO) leads to sympathetic hyperactivity with evidence of cardiac dysfunction by 4 mo of age. These mice provide a model system for evaluating non-pharmacological and pharmacological approaches for the prevention and treatment of heart failure. We investigated whether exercise training would improve the cardiac function and expression of myocardial Ca2+ handling proteins in KO. Methods and Results: We studied a cohort of congenic KO and their wild type (WT) controls over a period of 2 months (from 3-5 mo of age). Mice from both groups were randomly assigned into sedentary and trained. Exercise training (ET) consisted of 8-wk swimming session of 60 minutes, 5 days/wk. Blood pressure and heart rate (HR) were determined non-invasively by tail cuff. Cardiac contractility was evaluated by echocardiography. Exercise capacity was measured using a graded treadmill protocol. Cardiac sympathetic tone was estimated by pharmacological blockade of muscarinic receptors with atropine in the presence or absence of the b-adrenergic receptor antagonist propranolol. Cardiomyocyte cross-sectional diameter and cardiac collagen fraction were evaluated by optical microscopy. The protein expression of cardiac sarcoplasmic reticulum Ca2+ pump (SERCA2), phospholamban (PLB), phospho-Ser16-PLB, phospho-Thr17-PLB, sodium-calcium exchanger (NCX), ryanodine receptor (RYR), phospho-Ser2809-RYR2, and phosphatases 1 and 2A were analyzed using Western blotting technique. At 3 mo of age, no significant difference in blood pressure, FS and exercise capacity was observed between WT and KO mice, although KO mice had significantly higher HR. At 5 mo of age, when cardiac dysfunction is in an early stage, KO presented exercise intolerance and higher HR with significantly increased cardiac sympathetic tone (34%), cardiomyocyte cross-sectional diameter (15%) and cardiac collagen fraction (32%) when compared with WT mice. In addition, KO presented lower FS than WT mice (16± 0.2 vs. 20± 0.9%, p£0.05). The impaired FS in KO was associated with a reduction of SERCA2 (26%) and NCX (34%) expression. Conversely, phospho-Ser16-PLB and phospho-Ser2809-RYR2 was 56% and 42% increased in KO when compared with WT mice, respectively. ET prevented exercise intolerance and systolic dysfunction, normalized baseline HR and cardiac sympathetic tone, while it did not change cardiac collagen fraction. The improved ventricular function was associated with restored SERCA2 and phospho-Ser2809-RYR2 expression levels. Indeed, ET increased SERCA/PLB ratio and phospho-Ser16-PLB expression in 5 mo-old KO mice. Conclusion: Our data provide evidence of molecular mechanisms by which ET is a successful adjuvant to pharmacological therapy of HF.

ASSUNTO(S)

cardiac function treinamento físico insuficiência cardíaca função cardíaca ca2+ handling proteins exercise training heart failure proteínas envolvidas no controle do ca2+ intracelular

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