Abstract
Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr−/−) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr−/− mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease.
Highlights
Beta-blockers have cardioprotective properties, decrease mortality in patients with coronary artery disease (CAD), and are the recommended therapy for CAD and congestive heart failure [1,2]
MoTl.oSeciv. 2a0l1u9a, 2te0,txhFeOeRffPeEcEtRs RoEf VCIaEWv on cholesterol efflux, human monocytic THP-1 or hepatic3Hofu1h9-7 cells were treated with Cav
Our study found that Alix protein levels significantly increased in exosomes from Cav-treated THP-1 macrophages compared with vehicle control, which demonstrated the modulation of exosome biogenesis in Cav-treated THP-1 macrophages and partly explained the increased number of exosomes in Cav-treated cells
Summary
Beta-blockers have cardioprotective properties, decrease mortality in patients with coronary artery disease (CAD), and are the recommended therapy for CAD and congestive heart failure [1,2]. Cav and its metabolites prevent lipid peroxidation, such as oxidation of low-density lipoprotein (LDL) to oxidized LDL [4,5] It modulates cardiac inflammatory cytokines and fibrogenic cytokines, inhibits the expression of matrix metalloproteinase (MMP)-2 and MMP-9, and reduces tumor necrosis factor (TNF)-α-stimulated endothelial adhesiveness to human mononuclear cells [6,7,8]. Exosomes from dendritic cells activate nuclear factor-κB (NF-κB) pathway and upregulate expression of proinflammatory molecules, including vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM1), and E-selectin, which increase endothelial inflammation [19]. These results suggest the important role of exosomes that transfer bioactive cargos as intercellular communication in cardiovascular diseases. Based on the potential effects of Cav on the regulation of exosome functions and cholesterol efflux, we explored its effects on atherosclerosis in atherosclerosis-prone LDL receptor knockout (ldlr−/−) mice
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