Hypoxic preconditioning effects change in hypertrophied or insulin resistant rat hearts

Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education and Science of Ukraine

Cardioprotective mechanisms in the hypertrophied or insulin resistant heart is not fully elucidated. Insulin like growth factor IGF-1 through downstream kinases PI3K/Akt/GSK3beta is known to exert cardioprotective effects and regulate myocardial remodeling, glucose metabolism, cell survival, apoptosis, oxidative stress etc. The aim was to characterize IGF-1/PI3K/Akt-mediated cardioprotection in hypertrophied or insulin resistant hearts after hypoxic preconditioning in response to severe whole body hypoxia or isolated heart ischemia/reperfusion.

Experiments were performed in male adult Wistar rats, and SHR with long-term heart hypertrophy. Insulin resistance (IR) was induced by high fat diet (58% kcal from fat). The animals were exposed to hypoxic preconditioning using mild hypobaric hypoxia séances in barochamber (5600 m, 3 h). In 24 h, hearts were isolated with urethane narcosis and subjected to ischemia/reperfusion in a Langendorff mode, infarct size was detected with TTC staining. The other group of rats after preconditioning were subjected to severe hypoxia (9000 m, 3 h). Inhibitor of PI3K wortmannin or blocker of IGF-1R picropodophyllin were used for testing of cytoprotective signalling. Protein expression were examined using Western blotting.

In SHR, the myocardial expression of IGF-1 and Akt was lower by 42% or 63%, respectively, compared to Wistar. IR increased GSK-3beta expression and phosphorylation. Hypoxic preconditioning intensified IGF-1/PI3K/Akt-mediated cardioprotection, less pronounced in hypertrophied or insulin resistant hearts. Blockade of PI3K or IGF-1Rdecreased Akt phosphorylation, and abolished cytoprotective effects of preconditioning in view of mortality caused severe hypoxia, or of infarct size and cardiac function recovery in postischemic reperfusion. In SHR, hypoxia-induced cardioprotective effects and influences of the blockers were significantly reduced.

The long-term left ventricular hypertrophy is accompanied with reduction of IGF-1/IGF-1R/PI3K/Akt-dependent prohypertrophic and cardioprotective signalling. Hypoxic preconditioning mediated by IGF-1/PI3K/Akt-signalling loses its effectiveness during prolonged cardiac hypertrophy, as well as insulin resistance development.