Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53
Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53
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DOI：
10.5551/jat.6437
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Morimoto, Yasutsugu;Bando, Yasuko Kureishi;Murohara, Toyoaki
目的：糖尿病外周动脉疾病（PAD）易于侵袭，最近的报道表明，p53积累可能是糖尿病伤口愈合受损的原因。他汀类药物已被证明通过激活其特异性泛素连接酶MDM 2促进p53降解。本研究的目的是确定阿托伐他汀（ATR）是否通过MDM 2介导的p53减少来改善糖尿病PAD的结果。或载体2周，并进行缺血性后肢手术以产生糖尿病PAD模型。术后2周（13周龄）评估截肢的发生率和每个缺血肢体中p53/MDM 2信号的变化。ATR对年龄匹配（13周龄）和未手术的KK/Ay小鼠的胰岛素抵抗的影响进行了评估，通过葡萄糖耐量试验，循环脂联素浓度，和胰岛素信号（IRS-1/Akt磷酸化）的变化。所有糖尿病PAD模型均显示自截肢（100%）;然而，ATR治疗部分恢复了肢体缺失（41.7%）。ATR处理的KK/Ay缺血肢体中p53表达水平显著降低，MDM 2磷酸化水平显著升高，同时Akt激活。缺氧模拟铁螯合剂deferroxamine通过抑制Akt/MDM 2通路促进H9 c2成肌细胞中p53的积累，该通路由ATR恢复。结论：ATR被发现通过直接激活骨骼肌中的Akt/MDM 2通路来增加p53降解，从而恢复糖尿病缺血性肢体丧失。
Aim: 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.