Abstract
HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. However, the effect of AMPK activation on HDL functionality has not been established in vivo. We assessed the effects of pharmacological AMPK activation using A-769662, AICAR, metformin, and IMM-H007 on the atheroprotective functions of HDL in apoE-deficient (apoE−/−) mice fed with a high-fat diet. After administration, there were no changes in serum lipid levels among the groups. However, mice treated with AMPK activators showed significantly enhanced reverse cholesterol transport in vivo and in vitro. AMPK activation also increased the expression of ABCA1 and ABCG1 in macrophages and scavenger receptor class B type I and LCAT in the liver. HDL from AMPK activation mice exhibited lower HDL inflammatory index and myeloperoxidase activity and higher paraoxonase 1 activity than HDL from untreated mice, implying superior antioxidant and anti-inflammatory capacities. Pharmacological AMPK activation also induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE−/− mice. These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. This likely represents a key mechanism by which AMPK activation attenuates atherosclerosis.
Highlights
HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis
To investigate whether AMP-activated protein kinase (AMPK) activation could influence serum lipid in a mouse model of atherosclerosis, apoE / mice fed a high-fat diet were treated with vehicle, A-769662 (30 mg/kg, ip), aminoimidazole-4-carboxamide ribonucleotide (AICAR) (200 mg/ kg, ip), metformin (260 mg/kg, by gavage), or IMMH007 (200 mg/kg, by gavage)
Our results provide the first evidence that activation of AMPK using a variety of substances enhances HDL function, including its beneficial effects on reverse cholesterol transport (RCT), inflammation, and oxidative stress, all of which may contribute to a reduction in the formation of atherosclerotic lesions
Summary
HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. Pharmacological AMPK activation induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE / mice These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are Abbreviations: acLDL, acetylated LDL; AICAR, 5-aminoimidazole4-carboxamide ribonucleotide; AMPK, AMP-activated protein kinase; apoE / , apoE-deficient; Arg-1, arginase-1; CE, cholesteryl ester; HDL-C, HDL cholesterol; HII, HDL inflammatory index; HPODE, hydroperoxyoctadecadienoic acid; IL, interleukin; IMM-H007, triacetyl-3-hydroxyphenyladenosine; LDL-C, LDL cholesterol; LXR, liver X receptor; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MPO, myeloperoxidase; PAPC, 1-palmitoyl-2-arachidonyl-snglycero-3-phosphorylcholine, PEG, polyethylene glycol; PON1, paraoxonase 1; RCT, reverse cholesterol transport; SOD, superoxide dismutase; SR-BI, scavenger receptor class B type I; TC, total cholesterol; TG, triglyceride. Wang contributed to this work and should be considered co-first authors
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