Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages

Abstract

Elevated extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 (MMP-9) in oxidized low density lipoprotein (oxLDL)-induced macrophages leads to the progression of vulnerable plaques by degradation of the extracellular matrix. Our previous report showed that berberine regulates the expression of both EMMPRIN and MMP-9. In addition, P2X7 receptor (P2X7R) upregulation plays a crucial role in the development of atherosclerosis. However, it is unclear whether berberine regulated P2X7R level to inhibit both EMMPRIN and MMP-9 expession in macrophages. In the present study, we investigated the impact of berberine on P2X7R expression and the regulation of P2X7R in the expression of EMMPRIN and MMP-9 in oxLDL-induced macrophages. We found that P2X7R expression was increased, miR150-5p was reduced in oxLDL-induced macrophages, relatively. And A-438079 (a P2X7R inhibitor) or miR150-5p mimic treatment greatly reversed the upregulation of EMMPRIN and MMP-9 expression. Moreover, A-438079 significantly reduced oxLDL-induced AMP-activated protein kinase-α (AMPK-α) phosphorylation and reversed the activation of mitogen-activated protein kinase (MAPK), which in turn decreased the expression of EMMPRIN and MMP-9. These findings illustrate that P2X7R suppresses EMMPRIN and MMP-9 expression by inhibiting the AMPK-α/MAPK pathway in oxLDL-induced macrophages. Accordingly, exposure to berberine markedly upregulated miR150-5p, decreased P2X7R expression and downregulated MMP-9 and EMMPRIN levels in oxLDL-induced macrophages, resulting in AMPK-α/MAPK (JNK, p38, and ERK) inactivation. Overall, these results indicate that berberine increased miR150-5p level, subsequently inhibits P2X7R-mediated EMMPRIN and MMP-9 expression by suppressing AMPK-α and MAPK signaling in oxLDL-induced macrophages.

Atheroprotective Effects and Molecular Mechanism of Berberine

“…BBR significantly downregulated the expression of proinflammatory genes such as IL-1β, IL-6, MCP-1, inducible NOS, cyclooxygenase-2, and MMP-9 through AMPK activation in macrophages ( Jeong et al, 2009 ). In oxLDL-induced macrophages, BBR markedly upregulated miR150-5p level and decreased P2X7R-mediated extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP-9 expression ( Lu et al, 2021 ). In LPS-stimulated macrophages (RAW264.7), BBR treatment potently suppressed the expression of inflammatory cytokines such as TNF-α, IL-6, and MCP-1 through inhibition of NF-κB signaling via sirtuin 1-dependent mechanisms ( Zhang et al, 2017 ).…”

Small Molecule Compounds of Natural Origin Target Cellular Receptors to Inhibit Cancer Development and Progression

“…Berberine is a natural isoquinoline alkaloid produced by various plants, such as Berberis vulgaris and Coptis chinensis [ 78 ], and shows inhibitory activities against many types of cancers [ 79 , 80 ]. Lu et al demonstrated that berberine could effectively reduce P 2 X 7 R receptor expression in oxidized low-density lipoprotein-induced macrophages [ 81 ]. Consistently, Yao et al reported that berberine could markedly downregulate P 2 X 7 R expression in MDA-MB-231 cells, leading to reduced cell proliferation and migration [ 32 ].…”

Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage

“…In addition, berberine inhibits excessive autophagy, likely contributing to reduced myocardial ischemia-reperfusion injury in cardiac myocytes ( 94 ). Moreover, in an oxidized low-density lipoprotein (oxLDL)-induced macrophage model, berberine upregulated miR-150-5p level, subsequently inhibiting P2X7 receptor-mediated EMMPRIN and MMP-9 expression by suppressing AMPK-α and MAPK signaling, and exerting anti-atherogenic effects ( 95 ). Berberine has also been reported to have neuroprotective effects on ischemic brain injury by lowering intracellular ROS level, inhibiting cellular apoptosis ( 96 ), and promoting angiogenesis via AMPK-dependent microglial polarization to a homeostatic state following tMCAO ( 97 ).…”