Roles of cyclooxygenase-2 and phosphorylated Akt(Thr308) in cardiac hypertrophy regression mediated by left-ventricular unloading

Objectives Cyclooxygenase-2 is associated with cardiac hypertrophy during chronic heart failure and is regulated through the PI3K/Akt pathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylation was demonstrated in vitro. In chronic heart failure, left ventricular assist devices lead to...

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Published in:The Journal of thoracic and cardiovascular surgery 2007, Vol.133 (1), p.37-43
Main Authors: Wohlschlaeger, Jeremias, MD, Schmitz, Klaus Jürgen, MD, Palatty, Jenci, Takeda, Atsushi, MD, Takeda, Nobuakira, MD, Vahlhaus, Christian, MD, Levkau, Bodo, MD, Stypmann, Jörg, MD, Schmid, Christof, MD, Schmid, Kurt Werner, MD, Baba, Hideo Andreas, MD
Format: Article
Language:English
Subjects:
Adolescent
Adult
Biological and medical sciences
Cardiomegaly - etiology
Cardiomegaly - metabolism
Cardiomegaly - pathology
Cardiomegaly - physiopathology
Cardiothoracic Surgery
Cell Size
Cyclooxygenase 2 - metabolism
Heart Failure - complications
Heart Failure - physiopathology
Heart Failure - therapy
Heart-Assist Devices
Humans
Medical sciences
Middle Aged
Mitogen-Activated Protein Kinase 3 - metabolism
Myocardium - metabolism
Myocytes, Cardiac - pathology
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Surgery of the heart
Ventricular Function, Left
Ventricular Remodeling
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Summary:Objectives Cyclooxygenase-2 is associated with cardiac hypertrophy during chronic heart failure and is regulated through the PI3K/Akt pathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylation was demonstrated in vitro. In chronic heart failure, left ventricular assist devices lead to hypertrophy regression and molecular changes. Therefore, the expression of cyclooxygenase-2, phosphorylated Akt (p-Akt), and p-Erk 1/2, as well as cardiac hypertrophy before and after left ventricular assist device insertion, was investigated. Methods In myocardial tissue before and after left ventricular assist device insertion, the expression of cyclooxygenase-2, p-Akt(Thr308) , p-Akt(Ser473) , and p-Erk 1/2 was demonstrated by immunohistochemistry and quantified by morphometry. Colocalization of cyclooxygenase-2 and p-Akt(Thr308) was investigated by immuno-doublestaining. Results A significant decrease of cyclooxygenase-2, p-Akt(Thr308) , p-Akt(Ser473) , and p-Erk 1/2 protein expression and hypertrophy regression was observed after left ventricular assist device insertion. A significant correlation between cyclooxygenase-2 and p-Akt(Thr308) expression, as well as between cyclooxygenase-2 expression and cardiomyocyte diameter, was observed before, but not after, left ventricular assist device insertion. Only cyclooxygenase-2-positive cardiomyocytes showed significant hypertrophy regression on unloading. Sarcoplasmic colocalization of cyclooxygenase-2 and p-Akt(Thr308) is present before left ventricular assist device insertion and is decreased after unloading, whereas the normal myocardium is completely devoid of it. Conclusions Left ventricular assist device treatment is associated with a significant decrease of cyclooxygenase-2, p-Akt(Thr308) , p-Akt(Ser473) , and p-Erk 1/2, and cardiac hypertrophy regression of cyclooxygenase-2-positive cardiomyocytes. The significant correlation and colocalization in cardiomyocytes of cyclooxygenase-2 and p-Akt(Thr308) before left ventricular assist device insertion suggests a cross-talk between the 2 molecules in the progression of cardiac hypertrophy, which is reversibly regulated by the left ventricular assist device.
ISSN:0022-5223
1097-685X
DOI:10.1016/j.jtcvs.2006.07.042