Expression of Type IIA Secretory Phospholipase A 2 Inhibits Cholesteryl Ester Transfer Protein Activity in Transgenic Mice

Objective— High circulating levels of group IIA secretory phospholipase A 2 (sPLA 2 -IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA 2 -IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA 2 -IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA 2 -IIA triple transgenic mice (TTT) fed a Western-type diet. Approach and Results— sPLA 2 -IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice ( P 2 -IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA 2 -IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA 2 -IIA decreased CETP activity by reducing the acceptor properties of sPLA 2 -IIA–modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA 2 -IIA transgenic mice restored the acceptor properties for CETP. Conclusions— These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA 2 -IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.