Abstract
Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. On the other hand, it inhibits GAPDH by poly(ADP-ribosy)lation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC isoforms, hexosaminase pathway flux, and AGE formation is prevented by blocking PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in preclinical models. PARP activation is present in microvasculature of human diabetic subjects. The oxidative/nitrosative stress-PARP pathway leads to diabetes-induced endothelial dysfunction, which may be an important underlying mechanism for the pathogenesis of other diabetic complications (cardiomyopathy, nephropathy, neuropathy, and retinopathy). This review focuses on the role of PARP in diabetic complications and the unique therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1568-1580 |
| Number of pages | 13 |
| Journal | Antioxidants and Redox Signaling |
| Volume | 7 |
| Issue number | 11-12 |
| DOIs | |
| State | Published - Nov 2005 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
Cite this
Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications : Endothelial dysfunction, as a common underlying theme. / Pacher, Pál; Szabo, Csaba.
In: Antioxidants and Redox Signaling, Vol. 7, No. 11-12, 11.2005, p. 1568-1580.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications
T2 - Endothelial dysfunction, as a common underlying theme
AU - Pacher, Pál
AU - Szabo, Csaba
PY - 2005/11
Y1 - 2005/11
N2 - Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. On the other hand, it inhibits GAPDH by poly(ADP-ribosy)lation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC isoforms, hexosaminase pathway flux, and AGE formation is prevented by blocking PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in preclinical models. PARP activation is present in microvasculature of human diabetic subjects. The oxidative/nitrosative stress-PARP pathway leads to diabetes-induced endothelial dysfunction, which may be an important underlying mechanism for the pathogenesis of other diabetic complications (cardiomyopathy, nephropathy, neuropathy, and retinopathy). This review focuses on the role of PARP in diabetic complications and the unique therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.
AB - Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. On the other hand, it inhibits GAPDH by poly(ADP-ribosy)lation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC isoforms, hexosaminase pathway flux, and AGE formation is prevented by blocking PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in preclinical models. PARP activation is present in microvasculature of human diabetic subjects. The oxidative/nitrosative stress-PARP pathway leads to diabetes-induced endothelial dysfunction, which may be an important underlying mechanism for the pathogenesis of other diabetic complications (cardiomyopathy, nephropathy, neuropathy, and retinopathy). This review focuses on the role of PARP in diabetic complications and the unique therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.
UR - http://www.scopus.com/inward/record.url?scp=28844462418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28844462418&partnerID=8YFLogxK
U2 - 10.1089/ars.2005.7.1568
DO - 10.1089/ars.2005.7.1568
M3 - Article
VL - 7
SP - 1568
EP - 1580
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
SN - 1523-0864
IS - 11-12
ER -