We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3) and prolonged the lifespan of heart failure mice with genetic dilated cardiomyopathy or transverse aortic constriction-induced left ventricular hypertrophy. However, it remained unclear how DM-celecoxib regulated structure and function of cardiomyocytes and cardiac fibroblasts involved in cardiac remodeling. In the present study, therefore, we investigated the effect of DM-celecoxib on isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation, because DM-celecoxib prevented isoprenaline-induced cardiac remodeling in vivo. DM-celecoxib suppressed isoprenaline-induced neonatal rat cardiomyocyte hypertrophy by the inhibition of Akt phosphorylation resulting in the activation of GSK-3 and the inhibition of β-catenin and mammalian target of rapamycin (mTOR). DM-celecoxib also suppressed the proliferation and the production of matrix metalloproteinase-2 and fibronectin of rat cardiac fibroblasts. Moreover, we found that phosphatase and tensin homolog on chromosome 10 (PTEN) could be a molecule to mediate the effect of DM-celecoxib on Akt. These results suggest that DM-celecoxib directly improves the structure and function of cardiomyocytes and cardiac fibroblasts and that this compound could be clinically useful for the treatment of β-adrenergic receptor-mediated maladaptive cardiac remodeling.
Lemierre's syndrome (LS) is characterized by septic thrombophlebitis of the internal jugular vein with septicemia and metastatic infection following an oropharyngeal infection. LS is rare but can cause infective endocarditis (IE), complicating IE management. We report a case of IE secondary to thrombophlebitis in the left vertebral vein following pharyngitis (LS variant) with distinctively severe manifestations, including metastatic infection and severe neurological impairment with multiple cerebral infarctions. A pedunculated abscess was noted on the left ventricular free wall. Despite the patient's highly impaired consciousness level (i.e., comatose state), we performed early surgery to remove the abscess after excluding LS‐related brain complications. Preoperative antibiotics included clindamycin to cover LS‐related anaerobic bacteria, and thrombophlebitis required postoperative anticoagulation. By managing LS as well as IE, the infection was controlled, and the neurological status normalized. This report provides insights into the perioperative management of IE secondary to LS.
Background-Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3 in mouse models of genetic dilated cardiomyopathy and pressure-overload by transverse aortic constriction (TAC). In the present study, we investigated whether DM-celecoxib can also prevent isoproterenol (ISO) -induced cardiac remodeling. We also examined the effect of DM-celecoxib on cardiomyocyte autophagy in an attempt to identify the mechanisms by which DM-celecoxib prevents cardiac remodeling.Methods-For in vivo study, mice (C57BL/6J, male, 8 weeks of age) were randomly assigned into three groups: control group, ISO group and ISO plus DM-celecoxib group. ISO (20 mg/kg/day) was continuously injected using the Alzet micro-osmotic pump (model 1002) for 14 days. The mice received feed containing 1,000 ppm DM-celecoxib or vehicle during the whole period. Blood pressure was measured by the tail-cuff method before administration of ISO and on days 7 and 14. The mice were sacrificed on day 14 and their hearts were removed for analysis. For in vitro study, rat cardiomyocyte H9c2 cells were pretreated with DM-celecoxib (3 mmol/L) or vehicle for 3 h. The cells were then treated with ISO (5 mmol/L) for 48 h and cardiomyocyte sizes were measured. In both in vivo and in vitro studies, the expressions of proteins related to cardiac hypertrophy and autophagy signaling pathways were examined by western blotting analysis. Results-DM-celecoxib inhibited the increase of heart weight and myocyte cross-sectional area induced by ISO-treatment. It also prevented fibrosis in the left ventricle. In H9c2 cells, DM-celecoxib prevented the increase of cell surface area induced by ISO. Western blotting showed that DM-celecoxib activated GSK-3α and β by inhibiting Akt and thereby inhibited β-catenin. It also inhibited the phosphorylation of mTOR, an autophagy suppressor, and increased the expression of beclin-1, an autophagy marker. Conclusions-These results suggest that DM-celecoxib prevents cardiac hypertrophy by activating GSK-3 and modulating several signaling pathways including autophagy signaling pathways. Therefore, DM-celecoxib could be used as a lead compound to develop a new agent for preventing cardiac remodeling in heart diseases.
Background-We previously reported that 2,5-dimethylcelecoxib (DMC) activated glycogen synthase kinase-3 (GSK -3), a negative regulator of cardiac hypertrophy, in mice. In this study, we examined the effects of DMC on isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis using in vivo and in vitro systems.Methods-ISO (20 mg/kg/day) was administered to C57BL/6J mice using an osmotic pump, and DMC (1,000 ppm) was added into feed for 14 days. Mice were divided into 3 groups: Control, ISO and ISO+DMC. Primary neonatal rat ventricular cardiomyocytes (NRVCs) and adult rat cardiac fibroblasts (RCFs) were pretreated with DMC (3-20 mmol/L) from 1 hour before incubation with ISO (5 mmol/L) for 24 hours. NRVC sizes and RCF proliferation were measured and proteins were examined.Results-DMC prevented hypertrophy and fibrosis in vivo. DMC attenuated the enlargement of NRVCs by activating GSK-3 and suppressing β-catenin and mTOR. DMC also attenuated RCF proliferation by activating GSK-3 and suppressing cyclin D1. The direct involvement of GSK-3 was verified using a GSK-3 inhibitor SB216763. Conclusion-DMC prevented cardiac hypertrophy and fibrosis by activating GSK-3 and modulating downstream proteins.
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