ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome.
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.
Schneider
Jochen G
JG
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Finck
Brian N
BN
Ren
Jie
J
Standley
Kara N
KN
Takagi
Masatoshi
M
Maclean
Kirsteen H
KH
Bernal-Mizrachi
Carlos
C
Muslin
Anthony J
AJ
Kastan
Michael B
MB
Semenkovich
Clay F
CF
D000818:Animals; D051379:Mice; D001057:Apolipoproteins E / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D050197:Atherosclerosis / Q000188:drug therapy; D018797:Cell Cycle Proteins / Q000235:genetics; D002738:Chloroquine / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000187:drug effects; D008659:Metabolic Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D054637:Dual-Specificity Phosphatases
D001057:Apolipoproteins E; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D018797:Cell Cycle Proteins; D002738:Chloroquine; D004268:DNA-Binding Proteins; D010749:Phosphoprotein Phosphatases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C522152:Dusp22 protein, mouse; D054637:Dual-Specificity Phosphatases