Roles of cyclooxygenase-2 and phosphorylated Akt ( T hr308) in cardiac hypertrophy regression mediated by left-ventricular unloading

doi:10.1016/j.jtcvs.2006.07.042

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Roles of cyclooxygenase-2 and phosphorylated Akt ⁽ ^T ^hr308) in cardiac hypertrophy regression mediated by left-ventricular unloading

Jeremias Wohlschlaeger, MD^a^,_*, Klaus Jürgen Schmitz, MD^a^,_*, Jenci Palatty^a, Atsushi Takeda, MD^b, Nobuakira Takeda, MD^c, Christian Vahlhaus, MD^e, Bodo Levkau, MD^d, Jörg Stypmann, MD^e, Christof Schmid, MD^f, Kurt Werner Schmid, MD^a, Hideo Andreas Baba, MD^a^,_*

^a Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Germany
^b Faculty of Health Science, School of Physical Therapy, Gumma Paz College, Gumma, Japan
^c Department of Internal Medicine, Jikei University, Tokyo, Japan
^d Division of Pathophysiology, Department of Internal Medicine, University Hospital Essen, University of Duisburg-Essen, Germany
^e Department of Cardiology and Angiology, University Hospital Münster, Germany
^f Department of Thoracic and Cardiovascular Surgery, University Hospital Münster, Germany.

Received for publication May 10, 2006; revisions received June 29, 2006; accepted for publication July 31, 2006.

^_* Reprint requests: Hideo Andreas Baba, MD, Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany (Email: hideo.baba{at}medizin.uni-essen.de).

OBJECTIVES: Cyclooxygenase-2 is associated with cardiac hypertrophy duringchronic heart failure and is regulated through the PI3K/Aktpathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylationwas demonstrated in vitro. In chronic heart failure, left ventricularassist devices lead to hypertrophy regression and molecularchanges. Therefore, the expression of cyclooxygenase-2, phosphorylatedAkt (p-Akt), and p-Erk 1/2, as well as cardiac hypertrophy beforeand after left ventricular assist device insertion, was investigated.

METHODS: In myocardial tissue before and after left ventricular assistdevice insertion, the expression of cyclooxygenase-2, p-Akt^(Thr308), p-Akt ^(Ser473), and p-Erk 1/2 was demonstrated byimmunohistochemistry and quantified by morphometry. Colocalizationof 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 hypertrophyregression was observed after left ventricular assist deviceinsertion. A significant correlation between cyclooxygenase-2and p-Akt ^(Thr308) expression, as well as between cyclooxygenase-2expression and cardiomyocyte diameter, was observed before,but not after, left ventricular assist device insertion. Onlycyclooxygenase-2-positive cardiomyocytes showed significanthypertrophy regression on unloading. Sarcoplasmic colocalizationof cyclooxygenase-2 and p-Akt ^(Thr308) is present before leftventricular 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 witha significant decrease of cyclooxygenase-2, p-Akt ^(Thr308),p-Akt ^(Ser473), and p-Erk 1/2, and cardiac hypertrophy regressionof cyclooxygenase-2-positive cardiomyocytes. The significantcorrelation and colocalization in cardiomyocytes of cyclooxygenase-2and p-Akt ^(Thr308) before left ventricular assist device insertionsuggests a cross-talk between the 2 molecules in the progressionof cardiac hypertrophy, which is reversibly regulated by theleft ventricular assist device.