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 deviceslead 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 deviceinsertion, was investigated. Methods In myocardial tissue before and after left ventricular assist deviceinsertion, the expression of cyclooxygenase-2, p-Akt (Thr308) , p-Akt (Ser473) , and p-Erk 1/2 was demonstrated by immunohistochemistry 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 hypertrophy regression was observed after left ventricular assist deviceinsertion. 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 deviceinsertion. Only cyclooxygenase-2-positive cardiomyocytes showed significant hypertrophy regression on unloading. Sarcoplasmic colocalizationof cyclooxygenase-2 and p-Akt (Thr308) is present before left ventricular assist deviceinsertion and is decreased after unloading, whereas the normal myocardium is completely devoid of it. Conclusions Left ventricular assist devicetreatment 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 colocalizationin cardiomyocytes of cyclooxygenase-2 and p-Akt (Thr308) before left ventricular assist deviceinsertion suggests a cross-talk between the 2 molecules in the progression of cardiac hypertrophy, which is reversibly regulated by the left ventricular assist device.