Salsalate reduces atherosclerosis through AMPKβ1 in mice

Abstract

Objective Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an αβγ heterotrimer which inhibits macrophage inflammation and the synthesis of fatty acids and cholesterol in the liver through phosphorylation of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds to and activates AMPKβ1-containing heterotrimers that are highly expressed in both macrophages and liver, but the potential importance of AMPK and ability of salsalate to reduce atherosclerosis have not been evaluated. Methods ApoE −/− and LDLr −/− mice with or without (−/−) germline or bone marrow AMPKβ1, respectively, were treated with salsalate, and atherosclerotic plaque size was evaluated in serial sections of the aortic root. Studies examining the effects of salicylate on markers of inflammation, fatty acid and cholesterol synthesis and proliferation were conducted in bone marrow–derived macrophages (BMDMs) from wild-type mice or mice lacking AMPKβ1 or the key AMPK-inhibitory phosphorylation sites on ACC (ACC knock-in (KI)-ACC KI) or HMGCR (HMGCR-KI). Results Salsalate reduced atherosclerotic plaques in the aortic roots of ApoE −/− mice, but not ApoE −/− AMPKβ1 −/− mice. Similarly, salsalate reduced atherosclerosis in LDLr −/− mice receiving wild-type but not AMPKβ1 −/− bone marrow. Reductions in atherosclerosis by salsalate were associated with reduced macrophage proliferation, reduced plaque lipid content and reduced serum cholesterol. In BMDMs, this suppression of proliferation by salicylate required phosphorylation of HMGCR and the suppression of cholesterol synthesis. Conclusions These data indicate that salsalate suppresses macrophage proliferation and atherosclerosis through an AMPKβ1-dependent pathway, which may involve HMGCR phosphorylation and cholesterol synthesis. Since rapidly-proliferating macrophages are a hallmark of atherosclerosis, these data indicate further evaluation of salsalate as a potential therapeutic agent for treating atherosclerotic cardiovascular disease.

Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis

“…Inhibition of this regulatory mechanism results in the development and progression of atherosclerosis, suggesting that direct targeting of the AMPK-HMGCR signalling cascade may be an attractive therapeutic option for suppressing the development and progression of atherosclerosis and thus reduce cardiovascular risks. These findings provide a mechanistic basis to support the use of AMPK activators such as salsalate [ 25 ], O-304 [ 47 ] and PXL 770 [ 48 ] for reducing atherosclerotic cardiovascular disease risk.…”

“…In the context of atherosclerosis, AMPK has been shown to have multiple anti-atherogenic effects through its influence on inflammatory signalling [ 17 ], suppressing monocyte to macrophage differentiation [ 18 , 19 ], and increasing cholesterol efflux [ 20 , 21 ], which in combination, decreases foam cell formation and atherogenesis. In line with this, systemic infusion of direct or indirect AMPK activators such as A769662, salsalate or metformin has been shown to decrease lesion size in atherosclerotic prone mice [ [22] , [23] , [24] , [25] ].…”

Quercetin ameliorates chicken quality by activating the PI3K/PKB/AMPK signaling pathway in broilers

“…It was found that Schisandra chinensis fruit (SF) extract may decrease lipid accumulation by upregulating AMPK and downregulating HMGR ( 38 ). A study showed that salsalate reduces atherosclerosis through AMPK, which inhibits fatty acid and cholesterol synthesis through the phosphorylation of HMGCR in mice ( 47 ). Sterol regulatory element-binding protein (SREBP1) is found to particularly involve in the activation of the genes controlling fatty acid metabolism and de novo lipogenesis.…”

Salicylate induces epithelial actin reorganization via activation of the AMP-activated protein kinase and promotes wound healing and contraction in mice

“…However, the multifaceted effects of salicylate on various cell types remain unclear. Recently, a novel action of salicylate was discovered, with a recent study showing that it activates AMPK by binding to the A-769662 drug-binding site on the AMPK β1 subunit 16 . Through this mechanism, salicylate reportedly improves atherosclerosis and fatty liver 16 , 17 .…”

“…Recently, a novel action of salicylate was discovered, with a recent study showing that it activates AMPK by binding to the A-769662 drug-binding site on the AMPK β1 subunit 16 . Through this mechanism, salicylate reportedly improves atherosclerosis and fatty liver 16 , 17 . However, the role of salicylate in wound healing remains unclear.…”