Rutaecarpine Reverses the Altered Connexin Expression Pattern Induced by Oxidized Low-density Lipoprotein in Monocytes

Abstract

Adhesion of monocytes to the vascular endothelium is crucial in atherosclerosis development. Connexins (Cxs) which form hemichannels or gap junctions, modulate monocyte-endothelium interaction. We previously found that rutaecarpine, an active ingredient of the Chinese herbal medicine Evodia, reversed the altered Cx expression induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells, and consequently decreases the adhesive properties of endothelial cells to monocytes. This study further investigated the effect of rutaecarpine on Cx expression in monocytes exposed to ox-LDL. In cultured human monocytic cell line THP-1, ox-LDL rapidly reduced the level of atheroprotective Cx37 but enhanced that of atherogenic Cx43, thereby inhibiting adenosine triphosphate release through hemichannels. Pretreatment with rutaecarpine recovered the expression of Cx37 but inhibited the upregulation of Cx43 induced by ox-LDL, thereby improving adenosine triphosphate-dependent hemichannel activity and preventing monocyte adhesion. These effects of rutaecarpine were attenuated by capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. The antiadhesive effects of rutaecarpine were also attenuated by hemichannel blocker 18α-GA. This study provides additional evidence that rutaecarpine can modulate Cx expression through transient receptor potential vanilloid subtype 1 activation in monocytes, which contributes to the antiadhesive properties of rutaecarpine.

Biologically active quinoline and quinazoline alkaloids part II

“…137 Rutaecarpine decreased monocyte adhesion by reversing the altered connexin (Cx) expression also induced by ox-LDL. 138 In subsequent studies, the same group found that, more specifically, rutaecarpine pretreatment led to recovered Cx37 (artheroprotective) expression and inhibited Cx43 (artherogenic) upregulation, thus, improving adenosine triphosphate-dependent hemichannel activity. 138 In earlier studies, Xu et al found that rutaecarpine promoted reverse cholesterol transport (RCT) in vivo and suppressed atherosclerosis in ApoE/mice by promoting ABCA1 and SR-B1 activities within RCT.…”

“…138 In subsequent studies, the same group found that, more specifically, rutaecarpine pretreatment led to recovered Cx37 (artheroprotective) expression and inhibited Cx43 (artherogenic) upregulation, thus, improving adenosine triphosphate-dependent hemichannel activity. 138 In earlier studies, Xu et al found that rutaecarpine promoted reverse cholesterol transport (RCT) in vivo and suppressed atherosclerosis in ApoE/mice by promoting ABCA1 and SR-B1 activities within RCT. 139 It triggered promoters of ABCA1 and CLA-1 genes, and increased ABCA1 and SR-BI/CLA-1 expression in vitro related to liver X receptor alpha and liver X receptor beta.…”

“…The alkaloid effectively improved gap junction communication and significantly prevented endothelial dysfunction induced in HUVEC‐12 cells by exposure to oxidized low‐density lipoprotein (ox‐LDL) in vitro, which is related to regulation of connexin expression patterns via TRPV1 activation . Rutaecarpine decreased monocyte adhesion by reversing the altered connexin (Cx) expression also induced by ox‐LDL . In subsequent studies, the same group found that, more specifically, rutaecarpine pretreatment led to recovered Cx37 (artheroprotective) expression and inhibited Cx43 (artherogenic) upregulation, thus, improving ATP‐dependent hemichannel activity .…”

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

“…Rutaecarpine has been shown to be protective against atherosclerosis through regulating connexin expression in both ECs and monocytes. Pre-treatment of HUVECs with rutaecarpine prevents oxidised-LDL mediated endothelial damage, the reduction in Cx37 and Cx40 expression, and monocyte adhesion [ 142 ], whilst a later follow-up study found rutaecarpine pre-treatment of monocytes recovered Cx37 expression and anti-adhesive hemichannel ATP signalling following oxidised-LDL treatment [ 143 ]. Preventing endothelial oxidised-LDL damage and monocyte adhesion would therefore be useful to prevent the initiation of atherosclerotic plaque build-up, halting disease progression at its early stages.…”

Synthetic Fluororutaecarpine Inhibits Inflammatory Stimuli and Activates Endothelial Transient Receptor Potential Vanilloid-Type 1

“…Rutaecarpine (RUT) is one of the main bioactive ingredients extracted from the traditional medicine Evodia rutaecarpa [ 3 ] and exhibits a wide spectrum of biological activities [ 4 ]. RUT can improve atherosclerosis by preventing monocyte adhesion to the vascular endothelium [ 5 ]. RUT reduced the prostaglandin production of lipopolysaccharide (LPS)-activated RAW264.7 macrophages, but did not affect levels of cyclooxygenase (COX)-2 messenger (m)RNA or protein [ 6 ].…”