Atorvastatin prevents ischemic limb loss in type 2 diabetes: role of p53.
OBJECTIVE
Diabetic peripheral artery disease (PAD) is prone to be aggressive and recent reports have demonstrated that p53 accumulation may be responsible for impaired wound healing in diabetes. Statins has been demonstrated to facilitate p53 degradation by activating its specific ubiquitin ligase, MDM2. The aim of this study was to determine whether atorvastatin (ATR) improves the outcome of diabetic PAD through MDM2-mediated reduction of p53.


METHODS
Male KK/Ay mice (9 weeks old) were treated with ATR (2 mg/kg/day p.o.) or vehicle for 2 weeks and subjected to ischemic hindlimb operation to generate a diabetic PAD model. Incidences of amputation and changes of p53/MDM2 signaling in each ischemic limb were assessed 2 weeks after the operation (at 13 weeks of age). Effects of ATR on the insulin resistance of age-matched (13-week-old) and unoperated KK/Ay mice were assessed by the glucose tolerance test, circulating adiponectin concentration, and changes in insulin signaling (IRS-1/Akt phosphorylation).


RESULTS
In intact KK/Ay, ATR treatment mitigated insulin resistance without affecting cholesterol levels. All diabetic PAD models exhibited autoamputation (100%); however, ATR treatment partially restored the limb loss (41.7%). The p53 expression level in the ischemic limb of ATR-treated KK/Ay was significantly decreased and MDM2 phosphorylation level was markedly increased in tandem with the activation of Akt. Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt/MDM2 pathway, which was restored by ATR.


CONCLUSIONS
ATR was found to restore ischemic limb loss in diabetes by augmenting p53 degradation through direct activation of the Akt/MDM2 pathway in skeletal muscle.
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Yasutsugu
Y
Morimoto
Yasuko Kureishi
YK
Bando
Toshimasa
T
Shigeta
Akio
A
Monji
Toyoaki
T
Murohara
D000818:Animals; D000069059:Atorvastatin; D015153:Blotting, Western; D002478:Cells, Cultured; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005121:Extremities / Q000293:injuries / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007333:Insulin Resistance; D007511:Ischemia / Q000517:prevention & control*; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D000069059:Atorvastatin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt