Metformin directly suppresses atherosclerosis in normoglycaemic mice via haematopoietic adenosine monophosphate-activated protein kinase

Anusha Seneviratne, Luke Cave, Gareth Hyde, Soren Kragh Moestrup, David Carling, Justin C Mason, Dorian O Haskard, Joseph James Boyle

Research output: Contribution to journalArticlepeer-review


AIMS: Atherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque haemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and activating transcription factor 1 (ATF1). The antidiabetic drug metformin may also activate AMPK-dependent signalling. Hypothesis: Metformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, thereby suppresses atherogenesis.

METHODS AND RESULTS: Normoglycaemic Ldlr-/- hyperlipidaemic mice were treated with oral metformin, which profoundly suppressed atherosclerotic lesion development (P < 5 × 10-11). Bone marrow transplantation from AMPK-deficient mice demonstrated that metformin-related atheroprotection required haematopoietic AMPK [analysis of variance (ANOVA), P < 0.03]. Metformin at a clinically relevant concentration (10 μM) 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.

CONCLUSION: Metformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, and results in highly suppressed atherogenesis in hyperlipidaemic mice via haematopoietic AMPK.

Original languageEnglish
Pages (from-to)1295-1308
Number of pages14
JournalCardiovascular research
Issue number5
Publication statusPublished - 23 Apr 2021
Externally publishedYes


  • AMP-Activated Protein Kinases/genetics
  • Activating Transcription Factor 1/genetics
  • Animals
  • Aorta/drug effects
  • Aortic Diseases/enzymology
  • Atherosclerosis/enzymology
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Macrophages/drug effects
  • Metformin/pharmacology
  • Mice, Knockout
  • Phenotype
  • Phosphorylation
  • Plaque, Atherosclerotic
  • Receptors, LDL/genetics
  • Signal Transduction

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