TY - JOUR
T1 - ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome
AU - Schneider, Jochen G.
AU - Finck, Brian N.
AU - Ren, Jie
AU - Standley, Kara N.
AU - Takagi, Masatoshi
AU - Maclean, Kirsteen H.
AU - Bernal-Mizrachi, Carlos
AU - Muslin, Anthony J.
AU - Kastan, Michael B.
AU - Semenkovich, Clay F.
N1 - Funding Information:
This work was supported by the National Institutes of Health (P50 HL083762, AG20091, HL57278, CA71387, CA21765, ES05777), the Clinical Nutrition Research Unit (DK56341), the Diabetes Research and Training Center (DK20579), a Burroughs Wellcome Clinical Scientist Award in Translational Research, and by the American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children's Research Hospital. We thank Peter McKinnon for ATM mutant mice, and Chu Feng and Yimin Zhu for expert animal management.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
KW - HUMDISEASE
UR - http://www.scopus.com/inward/record.url?scp=33750449351&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2006.10.002
DO - 10.1016/j.cmet.2006.10.002
M3 - Article
C2 - 17084711
AN - SCOPUS:33750449351
SN - 1550-4131
VL - 4
SP - 377
EP - 389
JO - Cell metabolism
JF - Cell metabolism
IS - 5
ER -