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Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes.

Authors: Bitar, MS  Abdel-Halim, SM  Al-Mulla, F 
Citation: Bitar MS, etal., Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E951-63. doi: 10.1152/ajpendo.00189.2013. Epub 2013 Aug 13.
Pubmed: (View Article at PubMed) PMID:23941874
DOI: Full-text: DOI:10.1152/ajpendo.00189.2013

A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated beta-galactosidase activity and phospho-gamma-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes.

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RGD ID: 9588563
Created: 2014-10-30
Species: All species
Last Modified: 2014-10-30
Status: ACTIVE



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