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. 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. 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.
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 . 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 . 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 .
Which enzyme is inhibited by Varespladib?
Which enzyme is inhibited by Varespladib ?
secretory phospholipase A2
secretory phospholipase A2