Activation of adenosine A2_A receptors restores the altered cell-cycle machinery during impaired wound healing in genetically diabetic mice

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• 作者：Domenica Altavilla PhD^a ; Francesco Squadrito MD^a ; ^{Francesco.Squadrito@unime.it} ; Francesca Polito PhD^a ; Natasha Irrera JD^a ; Margherita Calò ; PhD^b ; Patrizia Lo Cascio PhD^c ; Mariarosaria Galeano MD^d ; Letizia La Cava JD^a ; Letteria Minutoli MD^a ; Herbert Marini MD^e ; Alessandra Bitto MD^a
• 刊名：Surgery
• 出版年：2011
• 出版时间：February 2011
• 年：2011
• 卷：149
• 期：2
• 页码：253-261
• 全文大小：1022 K

文摘

Background

Cyclins drive cell-cycle progression by associating with their kinase partners, cyclin-dependent kinases (CDK). We investigated cyclin D1/CDK6, cyclin E/CDK2 complexes, and the cell-cycle negative regulators p15 and p27 in an incisional skin wound model.

Methods

Wounds were produced on the back of female diabetic mice and their normoglycemic littermates. Animals were treated with polydeoxyribonucleotide (PDRN, 8 mg/kg/i.p.), an agonist of adenosine A2_A receptors, or its vehicle daily. Granulation tissue proliferation by Ki67 immunostaining, cyclin D/CDK6 and cyclin E/CDK2 complexes, and p21 and p16 proteins (Western blot analysis), and the histologic changes were assessed at different days (3, 6, and 12 days after injury).

Results

Numerous Ki67 positive cells were observed at day 3 and day 6 in the granulation tissue of normoglycemic mice. Ki67 positive cells were fewer in diabetic than in normoglycemic mice. PDRN increased Ki67 positive cells in diabetic mice. Normoglycemic mice showed the greatest upregulation of cyclin D1, CDK6, cyclin E, and CDK2 at day 6. Diabetic mice had a markedly lower expression of cyclin D1, CDK6, cyclin E, and CDK2 at day 6. They also showed a greater expression of p15 and p27 at day 6. PDRN administration in diabetic mice increased cyclin D1/CDK6 and cyclin E/CDK2 expression and reduced p15 and p27 inhibitors at day 6 after injury; moreover, it improved the impaired wound healing at day 12.

Conclusion

Our results suggest that adenosine A2_A receptor activation by PDRN might represent a therapeutic strategy to overcome the diabetes-impaired cell-cycle machinery.