ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome

Cell Metab. 2006 Nov;4(5):377-89. doi: 10.1016/j.cmet.2006.10.002.

Abstract

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • Atherosclerosis / drug therapy
  • Cell Cycle Proteins / genetics
  • Chloroquine / therapeutic use*
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Macrophages / drug effects
  • Metabolic Diseases / drug therapy*
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • Phosphoprotein Phosphatases / metabolism
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Signal Transduction*
  • Stress, Physiological / metabolism*
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics

Substances

  • Apolipoproteins E
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Chloroquine
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • JKAP protein, mouse
  • Phosphoprotein Phosphatases