Celecoxib and 2,5-Dimethyl-Celecoxib Prevent Cardiac Remodeling Inhibiting Akt-Mediated Signal Transduction in an Inherited Dilated Cardiomyopathy Mouse Model

Abstract

Celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug, has been shown to inhibit Akt and prevent cardiac remodeling in aortic banding-induced failing heart in mice. However, it may be difficult to use celecoxib for the treatment of heart failure because of thromboembolic adverse reactions. Since 2,5-dimethyl (DM)-celecoxib, a derivative unable to inhibit COX-2, has been also reported to inhibit Akt, we attempted to examine whether DM-celecoxib retains the ability to prevent cardiac remodeling and improve cardiac functions using a mouse model of inherited dilated cardiomyopathy (DCM). DM-celecoxib as well as celecoxib administered daily for 4 weeks inhibited Akt and subsequent phosphorylation of glycogen synthase kinase-3␤ and mammalian target of rapamycin. Furthermore, both celecoxib and DM-celecoxib inhibited the activities of nuclear factor of activated T cell and ␤-catenin and the expression of TCF7L2 (T-cell-specific transcriptional factor-7L2) and c-Myc, downstream mediators related to cardiac hypertrophy. Functional and morphological measurements showed that these compounds improved left ventricular systolic functions (ejection fraction: vehicle, 34.7 Ϯ 3.9%; 100 mg/kg celecoxib, 50.3 Ϯ 1.1%, p Ͻ 0.01; 100 mg/kg DM-celecoxib, 49.8 Ϯ 0.8%, p Ͻ 0.01), which was also evidenced by the decrease in ␤-myosin heavy chain and B-type natriuretic peptide, and prevented hypertrophic cardiac remodeling (heart/body weight ratio: vehicle, 10.4 Ϯ 0.7 mg/g; 100 mg/kg celecoxib, 8.0 Ϯ 0.3 mg/g, p Ͻ 0.01; 100 mg/kg DMcelecoxib, 8.2 Ϯ 0.1 mg/g, p Ͻ 0.05). As a consequence, both compounds improved the survival rate (vehicle, 45%; 100 mg/kg celecoxib, 75%, p Ͻ 0.05; 100 mg/kg DM-celecoxib, 70%, p Ͻ 0.05). These results suggested that not only celecoxib but also DM-celecoxib prevents cardiac remodeling and reduces mortality in DCM through a COX-2-independent mechanism involving Akt and its downstream mediators.

Celecoxib prevents pressure overload‐induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress

“…Moreover, randomized clinical trials have demonstrated that renal and cardiovascular safety of celecoxib has also become apparent, as well as its efficacy, tolerability, and safety in the elderly population . Growing evidence even indicated that celecoxib induces beneficial effects, rather than deleterious side effects, against cardiovascular stresses including inhibition of cardiac remodelling, cardiac fibrosis and cardiac inflammation . Therefore, in this study, we examined whether celecoxib could prevent pressure overload‐induced CH.…”

“…Research recently confirmed that celecoxib can have therapeutic effects on the heart. Specifically, celecoxib prevented cardiac remodelling in mice with inherited dilated cardiomyopathy . Additionally, an in vitro study indicated that celecoxib not only was anti‐inflammatory in the vascular endothelium but it also reduced cardiac cell hypertrophy and fibrosis induced by angiotensin and aldosterone .…”

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

“…In our study, we could not revert Mcl-1 downregulation and DMC-induced apoptosis with the proteasome inhibitor MG132, thus suggesting a proteasome-independent effect. The ability of DMC and OSU-03012 to inhibit AKT activity (Wang et al, 2008;Fan et al, 2011) may give part of the answer. Indeed, PI3K/AKT pathway can prevent ER stress through an accumulation of GRP78 (Dai et al, 2010), and, on the other hand, AKT is also activated by GRP78 (Lin et al, 2011).…”

Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

“…Given the fact that COX-2 regulates the phosphorylation of GSK-3β (15), it is conceivable that COX-2 may play a role in GSK-3β signaling and in the regulation of mitochondrial function during hepatic I/R injury. Thus, we used flurbiprofen, a nonselective COX-1/COX-2 inhibitor, to further gain insight into the role of COX in mitochondrial function relevant to hepatic I/R injury.…”