Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53

Abstract

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-weekold) 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.

Number of Endothelial Progenitor Cells in Peripheral Artery Disease as a Marker of Severity and Association with Pentraxin-3, Malondialdehyde-Modified Low-Density Lipoprotein and Membrane Type-1 Matrix Metalloproteinase

“…EPC is already known to promote vascular repair and vasculogenesis, and recent observations support the possibility that pentraxin-3 also possesses atheroprotective 26) and cardioprotective effects 27) , in contrast to other pentraxins, such as C-reactive protein and serum amyloid P. Therefore, increased EPC and pentraxin-3 could possibly play a atheroprotective role, thus correlating with the severity of PAD; however, our study only found that EPC and pentraxin-3 were upregulated in TASC A/B patients, and further studies might be required to reveal the detailed atheroprotective role in PAD, including the various other factors affecting PAD 28,29) . Both SDF-1 and vascular endothelial growth factor attract progenitor cells and are involved in homing, migration and mobilization from bone marrow to peripheral circulation 30,31) , contributing to vascular regeneration.…”

The role of the p53 tumor suppressor in metabolism and diabetes

“…These findings suggested that, in the context of diabetes, p53 might contribute positively to the development of insulin resistance through inducing oxidative stress in skeletal muscle. Consistent with this hypothesis, p53 was found to be an important target to control peripheral artery disease (PAD), which is an ischemic limb syndrome strongly associated with type 2 diabetes (Morimoto, et al 2011). Deferoxamine (DFX), a hypoxia mimetic and iron chelator, was used to mimic PAD in vitro and found to promote p53 accumulation in myoblast cells by suppressing MDM2 expression (Morimoto et al 2011).…”

“…In addition to its roles in diabetes risk and severity, p53 has also been shown to play an active role in these conditions by regulating apoptosis, cell cycle arrest, senescence and inflammation (Gurel, et al 2014; Jazayeri, et al 2008; Morimoto et al 2011; Nguyen, et al 2010; Samarakoon, et al 2012; Zhao, et al 2011). Targeting p53 to treat diabetes potentially offers extra benefits as an inclusive approach to alleviate both diabetes and downstream symptoms.…”

(−)-Epigallocatechin-3-gallate (EGCG) attenuates functional deficits and morphological alterations by diminishing apoptotic gene overexpression in skeletal muscles after sciatic nerve crush injury

“…These findings indicate that apoptosis has a physiologically important role in regulating denervationinduced muscle atrophy (Siu and Always 2005). Likewise, recent reports have implicated p53 accumulation in skeletal muscle for impaired wound healing in diabetic peripheral artery disease (Morimoto et al 2011). These studies are in line with our current findings that showed remarkable P53 gene overexpression levels in tibialis anterior muscles at days 3 and 7 after sciatic crush nerve injury.…”