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Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis

Vladimir R Babaev1, Lei Ding2, Youmin Zhang2

  • 1From the Atherosclerosis Research Unit, Department of Medicine (V.R.B., L.D., Y.Z., J.M.M., M.R.F.L.) and Pharmacology (M.R.F.L.), Vanderbilt University Medical Center, Nashville, TN; Center for Cancer Research, National Cancer Institute, Frederick, MD (P.C.L.); and Department of Medicine, Center of Preventive Cardiology, Oregon Health & Science University, Portland, OR (S.F.). vladimir.babaev@vanderbilt.edu macrae.linton@vanderbilt.edu.

Arteriosclerosis, Thrombosis, and Vascular Biology
|February 6, 2016
PubMed
Abstract

Insights

Genetic deficiency of IKKα (inhibitor of κB kinase alpha) in macrophages impairs Akt signaling, reducing monocyte and macrophage survival and decreasing early atherosclerosis development.

Area of Science:

  • Cellular biology
  • Immunology
  • Molecular biology

Background:

  • The IκB kinase (IKK) complex regulates transcription factor cascades crucial for cellular responses.
  • IKKα is linked to prosurvival pathways like PI3K/Akt, but its specific role in cell survival and atherosclerosis is unclear.
  • Macrophages are key players in atherosclerosis pathogenesis.

Purpose of the Study:

  • To investigate the role of IKKα signaling in macrophage survival and its impact on atherogenesis.
  • To elucidate the molecular mechanisms by which IKKα influences macrophage response to lipotoxicity and apoptosis.

Main Methods:

  • Utilized genetic IKKα deficiency and pharmacological IKK inhibition in mouse macrophages.
  • Assessed Akt S(473) phosphorylation, mTOR complex 2 signaling, and apoptosis resistance in IKKα-deficient macrophages.
  • Evaluated atherosclerosis progression in low-density lipoprotein receptor (LDLR)(-/-) mice reconstituted with IKKα(-/-) hematopoietic cells.

Main Results:

  • Genetic IKKα deficiency reduced Akt S(473) phosphorylation and mTOR complex 2 signaling in macrophages.
  • IKKα-null macrophages showed impaired Akt signaling and reduced resistance to apoptosis, especially under lipotoxic conditions.
  • In vivo, IKKα deficiency led to increased macrophage apoptosis in atherosclerotic lesions and reduced early atherosclerosis in LDLR(-/-) mice.

Conclusions:

  • Hematopoietic IKKα deficiency suppresses Akt signaling in monocytes and macrophages.
  • This suppression compromises monocyte/macrophage survival.
  • Reduced monocyte/macrophage survival due to IKKα deficiency leads to decreased early atherosclerosis.
Keywords:
apoptosisatherosclerosiscell survivalmacrophagesphosphorylation

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