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

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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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