The F2-isoprostane 8-iso-PGF2α attenuates atherosclerotic lesion formation in Ldlr-deficient mice - Potential role of vascular thromboxane A2 receptors

Abstract

The F2-isoprostane 8-iso-PGF_2α (also known as 15-F_2t-isoprostane, iPF_2α-III, 8-epi PGF_2α, 15(S)-8-iso-PGF_2α, or 8-Isoprostane), a thromboxane A₂ receptor (TP) agonist, stable biomarker of oxidative stress, and risk marker of cardiovascular disease, has been proposed to aggravate atherogenesis in genetic mouse models of atherosclerotic vascular disease. Moreover, the TP plays an eminent role in the pathophysiology of endothelial dysfunction, atherogenesis, and cardiovascular disease. Yet it is unknown, how the TP expressed by vascular cells affects atherogenesis or 8-iso-PGF_2α-related effects in mouse models of atherosclerosis. We studied Ldlr-deficient vascular endothelial-specific (EC) and vascular smooth muscle cell (VSMC)-specific TP knockout mice (TP^ECKO/Ldlr KO; TP^VSMCKO/Ldlr KO) and corresponding wild-type littermates (TP^WT/Ldlr KO). The mice were fed a Western-type diet for eight weeks and received either 8-iso-PGF_2α or vehicle infusions via osmotic pumps. Subsequently, arterial blood pressure, atherosclerotic lesion formation, and lipid profiles were analyzed. We found that VSMC-, but not EC-specific TP deletion, attenuated atherogenesis without affecting blood pressure or plasma lipid profiles of the mice. In contrast to a previous report, 8-iso-PGF_2α tended to reduce atherogenesis in TP^WT/Ldlr KO and TP^{EC KO}/Ldlr KO mice, again without significantly affecting blood pressure or lipid profiles of these mice. However, no further reduction in atherogenesis was observed in 8-iso-PGF_2α-treated TP^{VSMC KO}/Ldlr KO mice. Our work suggests that the TP expressed in VSMC but not the TP expressed in EC is involved in atherosclerotic lesion formation in Ldlr-deficient mice. Furthermore, we report an inhibitory effect of 8-iso-PGF_2α on atherogenesis in this experimental atherosclerosis model, which paradoxically appears to be related to the presence of the TP in VSMC.

Keywords: 8-iso-PGF(2α); Atherosclerosis; Endothelial cells; Endothelial dysfunction; F2-isoprostanes; Ldlr knockout mice; Thromboxane A(2) receptor; Vascular smooth muscle cells.