Expression of Type IIA Secretory Phospholipase A2 Inhibits Cholesteryl Ester Transfer Protein Activity in Transgenic Mice
Objective—High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet.
Approach and Results—sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-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 sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA–modified very low-density lipoprotein specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP.
Conclusions—These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.
- apolipoproteins E
- cholesteryl ester transfer proteins
- cholesterol, VLDL
- high-density lipoprotein cholesterol
- Received February 21, 2013.
- Accepted September 25, 2013.
- © 2013 American Heart Association, Inc.