Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2

Abstract

Macrophage survival is believed to be a contributing factor in the development of early atherosclerotic lesions. Dysregulated apoptosis of macrophages is involved in the inflammatory process of atherogenesis. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-inflammatory, antiplatelet, and antitumor activities. Here we showed that apigenin attenuated atherogenesis in apoE −/− mice in an in vivo test. In vitro experiments suggested that apigenin induced apoptosis of oxidized low density lipoprotein- (OxLDL-) loaded murine peritoneal macrophages (MPMs). Proteomic analysis showed that apigenin reduced the expression of plasminogen activator inhibitor 2 (PAI-2). PAI-2 has antiapoptotic effects in OxLDL-loaded MPMs. Enhancing PAI-2 expression significantly reduced the proapoptosis effects of apigenin. Molecular docking assay with AutoDock software predicted that residue Ser473 of Akt1 is a potential binding site for apigenin. Lentiviral-mediated overexpression of Akt1 wild type weakened the proapoptosis effect of apigenin in OxLDL-loaded MPMs. Collectively, apigenin executes its anti-atherogenic effects through inducing OxLDL-loaded MPMs apoptosis. The proapoptotic effects of apigenin were at least partly attributed to downregulation of PAI-2 through suppressing phosphorylation of AKT at Ser473.

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

“…Further studies showed that apigenin enhanced total superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) content in myocardium via repression of p38 MAPK signaling pathway, suggesting that apigenin can prevent cardiomyocytes from I/R-induced injury. Thus far, the studies regarding the athero-protective effects of apigenin and the underlying molecular mechanisms are limited to a certain extent [14,15]. Many kinds of flavonoid can exert athero-protection through regulation of lipid and cholesterol metabolism and macrophage ABCA1 expression [45][46][47], which makes us wonder whether apigenin can inhibit atherogenesis by maintaining cholesterol homeostasis.…”

“…It can prevent oxidized low-density lipoprotein (ox-LDL)-induced endothelial monocyte adhesion and improve endothelial dysfunction via inhibiting LDL oxidation and endothelial ox-LDL uptake in the early stages of AS [13]. Zeng et al revealed that apigenin attenuated atherogenesis through inducing apoptosis of ox-LDL-loaded murine peritoneal macrophages (MPMs) via down-regulation of plasminogen activator inhibitor 2 (PAI-2) in vivo [14]. Moreover, apigenin can lower the expression of pro-inflammatory cytokines and promote apoptosis of foam cells by inhibiting autophagy of foam cells during atherogenesis [15].…”

Apigenin Attenuates β-Receptor-Stimulated Myocardial Injury Via Safeguarding Cardiac Functions and Escalation of Antioxidant Defence System

“…On the whole, the treatments existing for ischaemic injury, including myocardial infarction, are directed towards reinstatement of blood supply to cardiac tissue and put off the damage imposing at the time of injury [7]. The existing management for MI includes beta blockers, ACE inhibitors/ARBs, nitrates and anti-thrombotic agents [8]. Though, in the face of the upgrading and ease of use of these therapies, the early death rate from acute MI is about 30 %, with more than half of these deaths occurring before the stricken individual reaches the hospital [9].…”

The progression of epithelial-mesenchymal transformation in gliomas

“…The increase of E-cadherin expression induced by matrin can be attributed to the inhibition of AKT signaling [44]. Apigenin which has been mentioned before can inhibit phosphorylation of AKT Ser473 and attenuate atherogenesis through inducing macrophage apoptosis [45].…”