PI3K(p110α) is essential for exercise-induced cardioprotection, and delivery of a caPI3K vector improved heart function in mice with established cardiac dysfunction after 10 weeks.
Does PI3K(p110α) activation mediate exercise-induced cardioprotection and can caPI3K gene therapy restore function in the failing heart in mice?
PI3K(p110α) is essential for exercise-induced cardioprotection, and its targeted activation via gene therapy can improve function in failing hearts in preclinical models.
BACKGROUND: Numerous molecular and biochemical changes have been linked with the cardioprotective effects of exercise, including increases in antioxidant enzymes, heat shock proteins, and regulators of cardiac myocyte proliferation. However, a master regulator of exercise-induced protection has yet to be identified. Here, we assess whether phosphoinositide 3-kinase (PI3K) p110α is essential for mediating exercise-induced cardioprotection, and if so, whether its activation independent of exercise can restore function of the failing heart. METHODS AND RESULTS: Cardiac-specific transgenic (Tg) mice with elevated or reduced PI3K(p110α) activity (constitutively active PI3K caPI3K and dominant negative PI3K, respectively) and non-Tg controls were subjected to 4 weeks of exercise training followed by 1 week of pressure overload (aortic-banding) to induce pathological remodeling. Aortic-banding in untrained non-Tg controls led to pathological cardiac hypertrophy, depressed systolic function, and lung congestion. This phenotype was attenuated in non-Tg controls that had undergone exercise before aortic-banding. Banded caPI3K mice were protected from pathological remodeling independent of exercise status, whereas exercise provided no protection in banded dominant negative PI3K mice, suggesting that PI3K is necessary for exercise-induced cardioprotection. Tg overexpression of heat shock protein 70 could not rescue the phenotype of banded dominant negative PI3K mice, and deletion of heat shock protein 70 from banded caPI3K mice had no effect. Next, we used a gene therapy approach (recombinant adeno-associated viral vector 6) to deliver caPI3K expression cassettes to hearts of mice with established cardiac dysfunction caused by aortic-banding. Mice treated with recombinant adeno-associated viral 6-caPI3K vectors had improved heart function after 10 weeks. CONCLUSIONS: PI3K(p110α) is essential for exercise-induced cardioprotection and delivery of caPI3K vector can improve function of the failing heart.
Weeks et al. (Sun,) conducted a other in Pathological cardiac remodeling and dysfunction. PI3K(p110α) modulation and rAAV6-caPI3K gene therapy vs. Non-transgenic controls and untrained mice was evaluated on Pathological cardiac remodeling and cardiac function. PI3K(p110α) is essential for exercise-induced cardioprotection, and delivery of a caPI3K vector improved heart function in mice with established cardiac dysfunction after 10 weeks.