Expression of type IIA secretory phospholipase A2 inhibits cholesteryl ester transfer protein activity in transgenic
Eva Hurt-Camejo1, Thomas Gautier, Birgitta Rosengren
1From the Department of Bioscience, CVMD iMED, AstraZeneca, R&D, Mölndal, Sweden (E.H.-C., B.R., M.B.); Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (T.G., A.D., U.J.F.T.); INSERM UMR866, Faculté de Médecine, Université de Bourgogne, Dijon, France (T.G.); Taconic, Hudson, NY (D.S.G.); and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia (D.J.R.).
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 lipoproteins 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.
