Protease activated receptor-2 (PAR-2) derived cycloxygenase-2 (COX-2) was recently implicated in a cardiac mast cell and fibroblast cross-talk signaling cascade mediating myocardial remodeling secondary to mechanical stress. We designed this study to investigate in vitro assays of isolated adult cardiac fibroblasts to determine whether binding of tryptase to the PAR-2 receptor on cardiac fibroblasts will lead to increased expression of COX-2 and subsequent formation of the arachodonic acid metabolite 15-dProstaglandin J 2 (15-d-PGJ 2 ). The effects of tryptase (100 mU) and co-incubation with PAR-2 inhibitor peptide sequence FSLLRY-NH 2 (10 -6 M) on proliferation, hydroxyproline concentration, 15-d-PGJ 2 formation and PAR-2/ COX-2 expression were investigated in fibroblasts isolated from 9 week old SD rats. Tryptase induced a significant increase in fibroproliferation, hydroxyproline, 15-d-PGJ 2 formation and PAR-2 expression which were markedly attenuated by FSLLRY. Tryptase-induced changes in cardiac fibroblast function utilize a PAR-2 dependent mechanism.

We hypothesized that acute pharmacological blockade of cyclooxygenase-2 (COX-2) using nimesulide (Nime) would prevent maladaptive changes in left ventricular (LV) structure and function secondary to abdominal aortic coarctation-induced pressure overload (PO). In vivo LV chamber dimension and function were assessed by pressure/volume admittance catheter at 14 days' postsurgery in three groups (n ≥ 6/group): sham-operated (Sham); untreated PO; and selective COX-2 inhibitor nimesulide-treated PO (PO + Nime; 25 mg/kg/d). Treatment was initiated 24 h prior to surgical induction of PO. Relative to Sham, there was a marked increase in LV mass index in the PO groups (2.2 ± 0.01 mg/g versus 2.9 ± 0.10 mg/g Sham versus PO, PO+Nime: 2.5 ± 0.03 mg/g). End diastolic volume, an indicator of chamber size, was significantly decreased in the PO animals compared with Sham (202 ± 17μL versus 143 ± 16 μL Sham versus PO, PO + Nime: 226 ± 9 μL). Collagen levels in PO rats assessed by hydroxyproline analysis were significantly elevated relative to Sham values. Nimesulide treatment attenuated: (1) the increase in LV mass index; (2) the reduction in end diastolic volume; and (3) the PO-induced increase in myocardial collagen. In summary, acute COX-2 inhibition with nimesulide attenuated the maladaptive changes in the LV after PO. Acknowledging the clinical failure of chronic COX-2 inhibitor use, we propose that acute treatment with COX-2 inhibition during the initial stages of cardiac remodeling can be beneficial in maintaining the normal cardiac structure and function during PO.

We sought to compare the effects of specific COX 2 inhibitors (Nimesulide) or Prostaglandin D synthase inhibitor (HQL 79) on cardiac remodeling secondary to pressure overload in rats. In vivo left ventricular (LV) structure and function was assessed by pressure/volume catheter at 28 days post surgery in six groups (n ≥ 6 per group): sham‐operated (Sham); untreated pressure overload (PO); Prevention or intervention groups treated with either NIMEsulide (25 mg/kg/d) or HQL 79 (10 mg/kg/d). The prevention strategy was initiated prior to induction of pressure overload and continued to day 14. Intervention treatment strategy started on day 14 post induction of pressure overload and continued till day 28. Both prevention and intervention NIME treatments attenuated the PO induced change in LV mass. Prevention treatment with HQL 79 attenuated this change. End diastolic volume was significantly decreased (by 29%) in PO group compared to Sham. Both treatment strategies with HQL 79 significantly attenuate this change. Prevention treatment with Nimesulide significantly attenuated the change in PO induced increase in total collagen levels, whereas both prevention and intervention treatment with HQL 79 significantly attenuated fibrosis. These findings indicate that cardiac remodeling during pressure overload occurs by Prostaglandin D2 mediated inflammatory pathway and can be attenuated using PGD synthase inhibitors.

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