Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms

Abstract

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.

Rosmarinic Acid Exhibits a Lipid-Lowering Effect by Modulating the Expression of Reverse Cholesterol Transporters and Lipid Metabolism in High-Fat Diet-Fed Mice

“…Furthermore, rosmarinic acid inhibits gluconeogenesis and insulin resistance in rats [25]. In our previous in vitro study, we reported that rosmarinic acid effectively reduces oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages by enhancing ABCA1 and ABCG1 expression [26]. In this study, we confirmed the protective effects of rosmarinic acid on hyperlipidemia in HFD-fed C57BL/6 mice and investigated the possible mechanism underlying the antihyperlipidemic effect of rosmarinic acid in vivo.…”

“…Some researchers have studied the effect of rosmarinic acid in animal model at various dose ranges between 2.5 and 200 mg/kg [23,[27][28][29][30]. Our previous in vitro study showed that rosmarinic acid effectively reduced oxLDL-induced cholesterol contents under HG conditions in macrophages at 50 and 100 µM [26]. Based on these reports, we investigated the protective effects of rosmarinic acid on hyperlipidemia in HFD-fed C57BL/6 mice at 50 mg/kg and 100 mg/kg.…”

Neuropeptide Y regulates cholesterol uptake and efflux in macrophages and promotes foam cell formation

“…It has been proven that the JAK2/STAT3 pathway upregulates the levels of ABCA1, ABCG1 and SR-BI and mediates cholesterol efflux in macrophages. 26 In this study, we found a reduction in ABCA1, found that NE appears to play a role in foam cell formation by preventing cholesterol efflux from macrophages by promoting ABCA1 degradation. 27 NPY, as a cotransmitter, is mainly found in postganglionic sympathetic neurons and is released simultaneously with norepinephrine (NE) in response to sympathetic stimulation.…”

Biomedical features and therapeutic potential of rosmarinic acid

“…The health-promoting benefits of RA could be based on scavenging reactive oxidation species, decreasing nitric oxide production, lipid peroxidation, increasing high-density lipoprotein, decreasing low-density lipoprotein levels, and deranged hemolysis (Baba et al 2004 ; Guo et al 2020 ). Nyandwi et al ( 2021b ) has reported lipid-lowering effects of RA through modulation of reverse cholesterol transport-related proteins, thereby combating hyperlipidemia-based disorders. RA also increased macrophage cholesterol influx via regulation of ABCA1 transporter expression through JAK2/STAT3, JNK, and PKC-p38 and ABCA2 expression JAK2/STAT3, JNK, and PKC-ERK1/2/p38 (Nyandwi et al 2021a ).…”