Phosphoinositide 3-kinase p110α is a master regulator of exercise-induced cardioprotection and PI3K gene therapy rescues cardiac dysfunction.
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.


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.
Baker IDI Heart and Diabetes Institute, University of Melbourne, Victoria 8008, Australia.
Kate L
KL
Weeks
Xiaoming
X
Gao
Xiao-Jun
XJ
Du
Esther J H
EJ
Boey
Aya
A
Matsumoto
Bianca C
BC
Bernardo
Helen
H
Kiriazis
Nelly
N
Cemerlang
Joon Win
JW
Tan
Yow Keat
YK
Tham
Thomas F
TF
Franke
Hongwei
H
Qian
Marie A
MA
Bogoyevitch
Elizabeth A
EA
Woodcock
Mark A
MA
Febbraio
Paul
P
Gregorevic
Julie R
JR
McMullen
D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D005082:Physical Exertion; D020127:Recovery of Function; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D018840:HSP70 Heat-Shock Proteins; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases