Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

Abstract

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.

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

“…It has further been suggested that exercise enhanced PI3K (p110a) activity could delay or prevent progression of dilated and hypertrophic cardiomyopathy (McMullen et al, 2007). Finally, a recent study has described that PI3K(p110a) gene therapy reduced cardiac dysfunction (Weeks et al, 2012). Our studies here show that reduction of Vcl levels in cardiac myocytes reduced PI3K activation, and inhibited autophagic and apoptotic signaling, compared to control cells with normal Vcl expression.…”

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…We recently generated a recombinant adeno-associated viral (rAAV) vector containing caPI3K that selectively transduced cardiac muscle, minimising the concern of PI3K's tumorigenic potential in other cell types [48]. rAAV6-caPI3K improved cardiac function in a mouse model of pressure overload and AAV-based therapies have entered clinical trials in heart failure patients [49,50]. Future studies will be required to assess whether rAAV6-caPI3K can improve function in a setting of diabetic cardiomyopathy.…”

Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice

“…The lack of an increased activation in the combined MI/exercise group might be explained by the different pathways induced by the different hypertrophy triggers. In fact, physiological stimuli like exercise act via IGF-I/PI3K p110␣ (10,47,81), whereas a pathological stimulus like MI rather activates PI3K p110␥ (57,59,63). The presence of both stimuli in the MI-runner group might then lead to a complex cross-talk wherein these two signaling pathways interfere.…”