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Qian Lingbo05.06.17
Protein Kinase C–Dependent Increase in Reactive Oxygen
Species Production in Vascular Tissues of Diabetes:
Role of Vascular NAD(P)H Oxidase
1
ONOO-NOO2
-.NOS
Short of L-arginine or H4B
Oxidationof H4B
Pathological circumstances
Damage
Effects of ROS on Vascular Cells
Background
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Major ROS in diabetic processes
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EDVD Atherosclerosis Hypertension
Hyperglycemia
ROS
PKC
?
etc.
Note: PKC- is more important in diabetic vascular damages
Diabetes Diabetic vascular complication
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diacylglycerol (DAG)-protein kinase C (PKC) pathway
Diabetic state
NAD(P)H oxidase
ROS Vascular damage
PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism for increased ROS in
diabetic vessels
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Activation of PKC in Diabetic Vascular Tissues
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aortic smooth muscle cells aortic endothelial cells
PKC-Dependent Activation of NAD(P)H Oxidase Induced by High Glucose
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Effect of STZ treatment on NAD(P)H oxidase activity (A) and on the NAD(P)H
oxidase subunit mRNA gp91phox (B)
NAD(P)H oxidase protein subunits in human diabetes Internal mammary arteries (IMA) and saphenous veins
(HSV)9
molecular mechanism
High glucose Rac-1
PKC inhibitors NAD(P)H oxidase
Ros
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saturated nonesterified fatty acids (NEFA) can stimulate de novo DAG synthesis and PKC activity in cultured aortic EC and smooth muscle cells
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Upregulation of NAD(P)H Oxidase Components in
Diabetic Vascular Tissues and Kidney
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NOX4 mRNA expression in kidney of control rats
and streptozotocininduced diabetic rats
p22phox mRNA expression in kidney of control rats and
streptozotocin induced diabetic rats
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A1 B1 A2 B2
Immunostaining analysis of NOX4 and p22phox expression (brown particles) in kidney of control rats (A1 , A2) and diabetic rats (B1 , B2)
NOX4 p22phox
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Effects of interventive insulin treatment on NOX4,p22phox and 8-OHdG expression levels in renal
tissue from diabetic rats
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Effect of PKC inhibitor on high glucose induced increasesin NOX4 (A) and p22phox (B) mRNA expression in cultured
mesangial cells
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Antioxidative Agents Targeting the Mechanism of NAD(P)H
Oxidase
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A. Effect of CGP41251 on spin clearance rates in streptozotocin
induced diabetic rats
B. Effect of apocynin on spin clearance rates in streptozotocin
induced diabetic rats
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40Effect of the inhibition
of PKC in vivo on vascular superoxide
production (red particles) in rat aorta as detected
with hydroethidine
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PKC inhibitor decreased expression of PKC-2 in high glucose incubated HUVECs
and improved EDVD in diabetic aorta
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Statins, angiotensin II-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) reduce ROS productions In diabetic vessels by inhibiting the activity of NAD(P)H oxidase
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?
High glucose level
PKC activation
ARB, ACEI
PKC inhibitors
NAD(P)H oxidase activation
Angiotensin II
ROS
Statin?
Possible antioxidative agents for diabetic vascular complications
Conclusion
PKC-NAD(P)H oxidase-ROS pathway a new target of antioxidative therapy for
preventing diabetic micro- or macro-vascular complications
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