In this section
@article{Boyle:2021:cvr/cvaa171,
author = {Boyle, J and Seneviratne, A and Cave, L and Hyde, G and Moestrup, SK and Carling, D and Mason, JC and Haskard, DO},
doi = {cvr/cvaa171},
journal = {Cardiovascular Research},
pages = {1295--1308},
title = {Metformin directly suppresses atherosclerosis in normoglycemic mice via haematopoietic Adenosine Monophosphate-Activated Protein Kinase (AMPK)},
url = {http://dx.doi.org/10.1093/cvr/cvaa171},
volume = {117},
year = {2021}
}
TY - JOUR
AB - AimsAtherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque hemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and ATF1. The anti-diabetic drug metformin may also activate AMPK-dependent signalling.HypothesisMetformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, and thereby suppresses atherogenesis.Methods and ResultsNormoglycemic Ldlr-/- hyperlipidemic mice were treated with oral metformin, which profoundly suppressed atherosclerotic lesion development (p < 5x10−11). Bone marrow transplantation from AMPK-deficient mice demonstrated that metformin-related atheroprotection required haematopoietic AMPK (ANOVA, p < 0.03). Metformin at a clinically relevant concentration (10μM) evoked AMPK-dependent and ATF1-dependent increases in Hmox1, Nr1h2 (Lxrb), Abca1, Apoe, Igf1 and Pdgf, increases in several M2-markers and decreases in Nos2, in murine bone marrow macrophages. Similar effects were seen in human blood-derived macrophages, in which metformin induced protective genes and M2-like genes, suppressible by si-ATF1-mediated knockdown. Microarray analysis comparing metformin with heme in human macrophages indicated that the transcriptomic effects of metformin were related to those of heme, but not identical. Metformin induced lesional macrophage expression of p-AMPK, p-ATF1 and downstream M2-like protective effects.ConclusionMetformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, and results in highly suppressed atherogenesis in hyperlipidemic mice via haematopoietic AMPK.Translational perspectiveThe work shows that oral antidiabetic drug metformin may suppress atherosclerotic lesion development via hematopoietic AMPK at clinically relevant concentrations, rather than via a hypoglycemic effect. Activating Transcription Factor 1 (ATF1) may mediate induction of key atheroprotective genes
AU - Boyle,J
AU - Seneviratne,A
AU - Cave,L
AU - Hyde,G
AU - Moestrup,SK
AU - Carling,D
AU - Mason,JC
AU - Haskard,DO
DO - cvr/cvaa171
EP - 1308
PY - 2021///
SN - 0008-6363
SP - 1295
TI - Metformin directly suppresses atherosclerosis in normoglycemic mice via haematopoietic Adenosine Monophosphate-Activated Protein Kinase (AMPK)
T2 - Cardiovascular Research
UR - http://dx.doi.org/10.1093/cvr/cvaa171
UR - https://academic.oup.com/cardiovascres/article/doi/10.1093/cvr/cvaa171/5871921
UR - http://hdl.handle.net/10044/1/80887
VL - 117
ER -