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  • IAA-94 australia br Conclusion We have demonstrated that ETB

    2021-10-09


    Conclusion We have demonstrated that ETB receptors negatively regulate the expression of AT1 receptors in renal proximal tubule IAA-94 australia from WKY rats but not in SHRs. Short-term activation of the ETB receptor increases AT1 receptor phosphorylation in WKY cells but decreases it in SHR cells. We conclude that ETB receptors regulate AT1 receptors by direct physical receptor interaction and receptor expression. The impaired natriuretic effect in SHRs may, in part, be related to impaired ETB receptor regulation of AT1 receptors.
    Acknowledgments
    Introduction Minimally modified low density lipoprotein (mmLDL) is a low density lipoprotein (LDL) with an oxidized lipid portion and can bind LDL receptors. The plasma level of mmLDL is significantly increased in acute and chronic coronary syndromes [1]. By promoting the adhesion of monocytes to endothelial cells [2], promoting the formation of foam cells [3], increasing the proliferation of smooth muscle cells [4] and inducing apoptosis of coronary artery endothelial cells and smooth muscle cells [5], mmLDL plays an important role in the development of cardiovascular disease. At the early stage of atherosclerosis, the adhesion of monocytes to vascular endothelial cells and their migration is the initiating step. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) can mediate this adhesion as well as the trans-endothelial migration and vascular smooth muscle cell proliferation and migration. The endothelin system is involved in the development and progress of cardiovascular disease, and endothelin-1 (ET-1) is a potent vasoconstrictor whose action is mediated by endothelin type A (ETA) receptors and endothelin type B (ETB) receptors, including both ETB1 receptors and ETB2 receptors. ETB1 receptors are present in endothelial cells and mediate vasodilation through the release of nitric oxide (NO) and prostacyclin (PGI2), while ETB2 receptors are found in vascular smooth muscle cells, mediate vasoconstriction with a strong plasticity, and are more commonly mentioned. ETB2 receptors are hardly expressed under normal physiological conditions but are often highly expressed in cardiovascular disease and mediate a strong contraction that appears to be a process developing from nothing [6], [7]. Mitogen-activated protein kinase (MAPK), which is activated by extracellular stimuli and mediates signal transduction within cells, is closely related to cardiovascular disease, including through extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways. The ERK1/2 signaling pathway is involved in the regulation of vascular ETB receptor expression [8], [9], [10], [11], [12]. High glucose [13] and particulate matter 2.5 (PM2.5) [14] can activate ERK1/2 and induce ICAM-1 and VCAM-1 expression in vascular endothelial cells. We found that mmLDL could activate the ERK1/2 pathway, thereby increasing mouse mesenteric artery α1 receptor expression and mediating vasoconstriction by intravenous tail injection of mmLDL [15]. We co-cultured mmLDL with the rat brain basilar artery and coronary artery in vitro and found that mmLDL increased the expression of ETA and ETB receptors and the contractile function of both the coronary artery and brain basilar artery, and this effect was related to the ERK1/2 pathway [16], [17], [18]. However, the results of the in vitro experiments are different from those on whole animals. We recently found that tail vein injection of mmLDL damaged the ultrastructure of vascular endothelial cells and vascular endothelium-dependent relaxation [19], and endothelial cell damage is the starting point of atherosclerosis. The mechanism by which mmLDL induces atherosclerosis and other cardiovascular diseases is still unclear. In this study, we examined whether mmLDL had an effect on ETB receptors and the possible molecular mechanisms involved at a whole-animal level to determine the site of action of mmLDL in the vessels and provide a breakthrough point for the prevention and treatment of vascular disease.