Abstract 3929: Daily Therapy With the Phospholipase A2 Inhibitor, PX-18, Improves the Chronic Inflammatory State in Obese Mice and Reduces Infarct Size Following Ischemia/Reperfusion
Background: The low-molecular weight, calcium-dependent type IIA secretory phospholipase A2 (sPLA2-IIA) has been implicated in irreversible cell damage following ischemia-reperfusion (I/R) injury primarily due to the release of inflammatory mediators and direct cytotoxicity to cells. We hypothesized that chronic daily therapy with the sPLA2-IIA inhibitor, PX-18, in obese type II diabetic mice will attenuate markers of obesity-induced inflammation and reduce infarct size (IS) in a Langendorff model of I/R.
Methods and Results: Adult male homozygous leptin receptor null (db/db) mice at a mean age of 10 weeks were treated with PX-18 (30 mg/kg ip) or with 10% DMSO for 28 days. Upon completion of therapy, all hearts were isolated for 30 min global ischemia and 60 min reperfusion in Langendorff mode. Serum samples were taken for cytokine analysis using the Bio-Rad Bioplex Pro-Magnetic Assay. IS was measured by computer morphometry of tetrazolium stained sections. Treatment with PX-18 significantly reduced IS compared to DMSO (14.3%±1.9 vs. 44.7±4.2%, P<0.001) [Fig 1A⇓]. Markers of inflammation including tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-3, IL-5, IL-9, IL-10, IL-12, and IL-13 were also significantly reduced as compared to the DMSO treatment group [Fig 1B⇓].
Conclusion: These results indicate that chronic administration with PX-18 may be an effective therapy in reducing circulating levels of inflammatory cytokines in obese db/db mice while providing an impressive infarct-sparing effect after ex vivo I/R.