P364Cardioprotective signaling in preconditioned and hypertrophied heart

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Abstract

Purpose: Despite the fact that myocardial preconditioning investigations led to an explanation of the many defense mechanisms in the heart, it remains unclear how they function in the hypertrophied myocardium.

Methods: In male Wistar rats aged 6 months, hypertrophy of left heart ventricle was induced by isoproterenol (5 mg/kg, 7 days). For hypertrophy of right ventricle, rats were acclimated to high altitude hypoxia (2100 m a.s.l.). Delayed cardioprotection was induced by preconditioning with whole body hypoxia séance (10% O2, 3 h). Dynamic changes in protein expression in left and right ventricles were examined by Western blotting.

Results: In control animals, preconditioning up to 3-5 days increased the expression of Akt kinase and its phosphorylation, expression of down-stream enzyme eNOS, as well as its scaffold-proteins caveolin-3, and dystrophin. In the right ventricle, cardioprotective effects manifested earlier and stronger, than in left one.

In isoproterenol-treated rats, expression and phosphorylation of Akt were 1,6-2,2-fold enhanced only in left ventricle in association with its hypertrophic response up to 7 days. In 5-7 days, expression and activation of anti-hypertrophic kinase GSK-3beta, and caveolin-3 was stimulated in both ventricles. After 7 days, adverse depletion of dystrophin expression was found.

Under the chronic hypoxic conditions, dystrophin and GSK-3beta expression was decreased in the hypertrophied right ventricle. However, expression of Akt kinase was 1.4-fold increased in the right ventricle, and 6,2-fold - in the left one. In response to preconditioning, induction of Akt was diminished, but induction of GSK-3beta was twofold intensified, than in rats without hypertrophy. Dystrophin demonstrated deferred and depressed induction in hypertrophic myocardium.

Conclusions: Delayed cardioprotection induced by hypoxic preconditioning mediates by up-regulation of Akt/eNOS way, which may be supported by dystrophin/caveolin-3-formed signalosomes in cardiomyocytes. Left or right ventricle hypertrophy associates with enhanced expression of proliferative Akt kinase, but is accompanied with reduction of Akt-mediated cytoprotective response. Instead, the cellular response is shifted to GSK-3beta-mediated anti-hypertrophic reaction or apoptosis. Maintenance of scaffold-protein protective response in hypertrophied myocardium is limited, especially by dystrophin. The results demonstrate significant changes of cardioprotective response in hypertrophied heart based on rebuilding of signal ways including expression of signal proteins and its spatial and functional regulation.

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