Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.
Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.
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增强的整联蛋白α4β1介导的粘附有助于糖尿病中内皮祖细胞的动员缺陷。
DOI：
10.2337/db16-0634
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发表时间：
2016-11
期刊：
影响因子：
7.7
通讯作者：
O'Toole TE
中科院分区：
文献类型：
--
作者：
Abplanalp WT;Conklin DJ;Cantor JM;Ginsberg MH;Wysoczynski M;Bhatnagar A;O'Toole TE
糖尿病与循环内皮祖细胞（EPCs）的缺陷有关，这归因于它们从骨髓中动员的缺陷。这种动员缺陷的基础尚不完全清楚，我们试图确定高血糖状况是否会增强EPC粘附。我们发现在高糖培养基中培养EPCs增加了与骨髓基质细胞的粘附。这种增强的粘附与蛋白激酶A调节亚基1β (PRKAR1β)的表达降低、蛋白激酶A （PKA）的激活以及丝氨酸988上α4整合素的磷酸化有关。通过PKA抑制剂、PRKAR1β过表达或磷酸化缺陷α4-整合素变体（α4[S988A]）的表达，这种增强的粘附被逆转。通过1型糖尿病模型，我们发现α4（S988A）表达的小鼠比野生型小鼠有更多的循环EPCs。此外，糖尿病α4（S988A）小鼠后肢缺血后血运重建增强。因此，我们已经确定了一种新的信号机制，激活糖尿病中的PKA（抑制调节亚基的下调），导致循环EPCs的缺陷和血管修复受损，这可以通过α4整合素突变逆转。
Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation.
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影响因子：
15.9
作者：
Gallagher, Katherine A.;Liu, Zhao-Jun;Velazquez, Omaida C.
通讯作者：
Velazquez, Omaida C.
影响因子：
20.3
作者：
Hattori, K;Heissig, B;Moore, MAS
通讯作者：
Moore, MAS
影响因子：
7.7
作者：
Loomans, CJM;de Koning, EJP;van Zonneveld, AJ
通讯作者：
van Zonneveld, AJ
影响因子：
17.1
作者：
Ferraro F;Lymperi S;Méndez-Ferrer S;Saez B;Spencer JA;Yeap BY;Masselli E;Graiani G;Prezioso L;Rizzini EL;Mangoni M;Rizzoli V;Sykes SM;Lin CP;Frenette PS;Quaini F;Scadden DT
通讯作者：
Scadden DT
DOI：
10.1083/jcb.200304031
发表时间：
2003-08-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goldfinger LE;Han J;Kiosses WB;Howe AK;Ginsberg MH
通讯作者：
Ginsberg MH