Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress.
OBJECTIVE
The maladaptive response to biomechanical stress is a fundamental response in heart disease. Loss of the 3'-lipid phosphatase, phosphatase and tensin homolog deleted on chromosome ten (PTEN), is associated with increased phosphorylation of Akt/protein kinase B and glycogen synthase kinase-beta. We hypothesize that these key changes will halt the development of pathological hypertrophy and the progression to heart failure in response to pressure overload.


RESULTS
In mice, muscle-specific knockout of PTEN, mckCRE-PTEN(flox/flox) (PTEN KO), resulted in basal hypertrophy and mild reduction in left ventricular (LV) systolic function. Male mice were subjected to aortic banding (AB) or sham operation. In contrast to mckCRE-PTEN(+/+) control mice, pressure overload in PTEN KO mice resulted in reduced pathological hypertrophy, less interstitial fibrosis, and reduced apoptosis with a marked preservation of LV function. Western blot analysis of mitogen-activated protein kinase (MAPK) signalling showed equivalent phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 with markedly reduced phosphorylation of jun N-terminal kinase (JNK)1 and JNK2, and p38 in PTEN KO mice subjected to AB. Loss of PTEN was associated with increased expression of the proangiogenic factors, vascular endothelial growth factor-A and angiopoietin-2, with preservation of the myocardial capillary density in response to pressure overload. Moreover, banded PTEN KO mice maintained the expression of several key metabolic genes that are known to be dysregulated in heart failure. In contrast, a subpressor dose of the G protein-coupled receptor (GPCR) agonist angiotensin II (Ang II) leads to increased pathological hypertrophy and MAPK activation in PTEN KO mice.


CONCLUSIONS
Loss of PTEN prevents the development of maladaptive ventricular remodelling with preservation of angiogenesis and metabolic gene expression in response to pressure overload but not in response to the GPCR agonist, Ang II. Inhibition of PTEN signalling in the heart may represent a novel approach to slow the progression of heart failure in response to pathological biomechanical stress.
Oudit
Gavin Y
GY
Division of Cardiology, Department of Medicine, Rm 7326, Medical Sciences Building, One King's College Circle, University of Toronto, Toronto, Canada M5S 1A8. gavin.oudit@utoronto.ca
Kassiri
Zamaneh
Z
Zhou
Joyce
J
Liu
Qiao C
QC
Liu
Peter P
PP
Backx
Peter H
PH
Dawood
Fayez
F
Crackower
Michael A
MA
Scholey
James W
JW
Penninger
Josef M
JM
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D017209:Apoptosis; D015153:Blotting, Western; D003250:Constriction; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism / Q000235:genetics; D005355:Fibrosis; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D042501:Angiogenic Proteins; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse