TY - JOUR
T1 - Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes
AU - Abdelsaid, Mohammed
AU - Prakash, Roshini
AU - Li, Weiguo
AU - Coucha, Maha
AU - Hafez, Sherif
AU - Johnson, Maribeth H.
AU - Fagan, Susan C.
AU - Ergul, Adviye
N1 - Funding Information:
Funding. This work was supported in part by an American Heart Association Postdoctoral Fellowship (14POST19580004 to M.A.); American Heart Association Predoctoral Fellowships (12PRE11300001 to M.C. and 13PRE17090026 to S.H.); Veterans Affairs Merit Awards (BX000347, BX00891) and National Institutes of Health award (NS-063965) to S.C.F.; and a Veterans Affairs Research Career Scientists award and National Institutes of Health awards (NS-070239, NS-083559) to A.E. A.E. is a Research Career Scientist at the Charlie Norwood Veterans Administration Medical Center in Augusta, GA. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.A. collected and analyzed the data and wrote the manuscript. R.P. and W.L. collected the data. M.C. and S.H. collected and analyzed the data. M.H.J. performed statistical analyses and reviewed the manuscript. S.C.F. reviewed the manuscript. A.E. wrote and reviewed the manuscript. A.E. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
This work was supported in part by an American Heart Association Postdoctoral Fellowship (14POST19580004 to M.A.); American Heart Association Predoctoral Fellowships (12PRE11300001 to M.C. and 13PRE17090026 to S.H.); Veterans Affairs Merit Awards (BX000347, BX00891) and National Institutes of Health award (NS-063965) to S.C.F.; and a Veterans Affairs Research Career Scientists award and National Institutes of Health awards (NS-070239, NS- 083559) to A.E. A.E. is a Research Career Scientist at the Charlie Norwood Veterans Administration Medical Center in Augusta, GA.
PY - 2015/5
Y1 - 2015/5
N2 - Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38- mitogen- Activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin- Treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage, and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20- Tetrakis(4- sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes.
AB - Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38- mitogen- Activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin- Treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage, and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20- Tetrakis(4- sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes.
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UR - http://www.scopus.com/inward/citedby.url?scp=84981508397&partnerID=8YFLogxK
U2 - 10.2337/db14-1423
DO - 10.2337/db14-1423
M3 - Article
C2 - 25524911
AN - SCOPUS:84981508397
SN - 0012-1797
VL - 64
SP - 1804
EP - 1817
JO - Diabetes
JF - Diabetes
IS - 5
ER -
