Abstract 1435: Reduction in Myocardial Ischemia-reperfusion Injury in Group X Secretory Phospholipase A2-deficient Mice
Secretory phospholipase A2 (sPLA2) plays a critical role in the pathophysiology of cardiovascular diseases. Among several types of sPLA2, the recently cloned group X sPLA2 (sPLA2-X) has the most potent hydrolyzing activity on phosphatidylcholine and elicits a marked release of arachidonic acid (AA) from cell surface membranes. To investigate the potential role of sPLA2-X in ischemic heart disease, we generated mice that lack sPLA2-X and studied their response to myocardial ischemia-reperfusion.
Methods and Results: The sPLA2-X-deficient mice had no significant abnormality in major tissues. In myocardial ischemia-reperfusion model that was made by 1 hr ligation of left anterior descending coronary artery, followed by 24 hrs reperfusion, the sPLA2-X-deficient mice had a 33% reduction in myocardial infarction size, a 34% preservation of echocardiographic LV ejection fraction, and a 43% decrease in myocardial myeloperoxidase activity, a marker of neutrophils accumulation, as compared with wild-type mice. sPLA2-X in neutrophils accounts for these results because
in the infarcted myocardium of wild-type mice, sPLA2-X was expressed in neutrophils but not in myocardial tissues or platelets and was undetectable in plasma,
the extent of myocardial ischemia-reperfusion injury was comparable between sPLA2-X-deficient mice and wild-type mice in the Langendorff experiments using the isolated hearts perfused by PBS buffer.
The isolated neutrophils from sPLA2-X-deficient mice had lower activities of respiratory burst, elastase release, and migration in response to OZ, C5a, and FMLP than neutrophils from wild-type mice (by −20 ~ −50%). The exogenous addition of either AA or sPLA2-X reversed the response of the sPLA2-X-deficient neutrophils to the external stimuli. Furthermore, systemic administration of LY374388, an inhibitor of sPLA2-X, reduced myocardial ischemia-reperfusion injury by 51% as well as cytotoxic activity of neutrophils in wild-type mice.
Conclusions: Myocardial ischemia-reperfusion injury was attenuated in sPLA2-X-deficient mice, and the suppression of neutrophils function in sPLA2-X-deficient mice accounts for this attenuation. The inhibition of sPLA2-X might have therapeutic value in acute myocardial infarction.