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Vascular effects of PPAR  activation: Endothelial function. PPAR agonists. Improved substrate metabolism.  Thrombosis  Plaque stability.  Cell recruitment and activation .  Inflammatory response .  Vasoconstriction  Cell migration.  Foam cell formation  Cholesterol efflux.

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Vascular effects of

PPAR activation:

Endothelial function


Potential vascular benefits of ppar activation

PPAR agonists

Improved substrate metabolism

 Thrombosis

 Plaque stability

 Cell recruitment and activation

 Inflammatory response

 Vasoconstriction

 Cell migration

 Foam cell formation

 Cholesterol efflux

 Atherogenesis

Potential vascular benefits of PPAR activation

Cariou B et al. Br J Diabetes Vasc Dis. 2005;5(3):126-32.


Evidence on PPAR activation and

favourable effects on endothelial dysfunction

  • PPARs involved in different dimensions of endothelial dysfunction: contractile, thrombotic, permeability and proliferative

  • PPAR ligands stimulate EC Nitric oxide release

  • PPAR agonists ameliorate EC activation via inhibition of DAG-PKC-b signalling pathway

  • Clinical trials in diabetic & nondiabetic patients

Cariou B et al. Br J Diabetes Vasc Dis. 2005;5:126-32.


Ppar activation and endothelial function
PPAR activation and endothelial function

Pioglitazone

Pioglitazone

Pioglitazone

Placebo

Placebo

Placebo

400

600

400

P=0.01

P=0.31

P=0.07

300

300

500

Forearm Blood Flow

(% Increases from baseline)

200

200

400

100

100

300

0

0

0

0.8

30

15

400

1.6

3.2

100

7.5

200

Sodium Nitroprusside

(ng/min)

Bradykinin

(ng/min)

Acetylchloline

(µg/min)

Campia U et al. Circulation 2006; 113: 867-75


Endothelial dysfunction by tnf infusion

NO dependent vasodilation

100

Pioglitazone

80

+TNF (10ng/min/2h)

60

Placebo

40

MC % change

Placebo

+TNF (10ng/min/2h)

20

0

0

0,6

1,8

6

-20

Dosis serotonin

(ng/100mlFAV/min)

Endothelial dysfunction by TNF-infusion

Martens FM, EurHeart J. 2006;27(13):1605-9


Ppar activation blunts progression of carotid atherosclerosis
PPAR  activation blunts progression of carotid atherosclerosis

N = 173 with type 2 diabetes

ns

0.08

0.04

CarotidIMT (mm)

0.00

P < 0.001

–0.04

–0.08

–0.12

P < 0.005

–0.16

0

12

24

Weeks

Glimepiride 2.7 mg

Pioglitazone 45 mg

Langenfeld MR et al. Circulation. 2005;111:2525-31.


Tzds impact carotid imt
TZDs impact carotid IMT

Patients

(Duration)

Study (year)

Treatment

 IMT (mm)

Minamikawa(1998)

TRO 400 mgUsual care

DM2 (6 mo)

0.08, TRO0.03, Usual careP < 0.001

Koshiyama(2001)

PIO 30 mgUsual care

DM2(6 mo)

0.08, PIO

0.02, Usual careP < 0.001

Sidhu(2004)

ROSI 8 mgPlacebo

Stable CAD(48 wk)

0.01, ROSI

0.03, PlaceboP = 0.03

Langenfeld(2005)

PIO 45 mgGLIM 2.7 mg (mean)

DM2

(6 mo)

0.05, PIO

0.01, GLIMP < 0.005

TRO = troglitazone ROSI = rosiglitazone

PIO = pioglitazone GLIM = glimepiride

Minamikawa J et al. J ClinEndocrinolMetab 1998; Koshiyama H et al. J ClinEndocrinolMetab2001;

Sidhu JS et al. ArteriosclerThrombVascBiol2004;Langenfeld MR et al. Circulation 2005.


Tzds consistently reduce restenosis after coronary stenting in patients with diabetes

TRO*

TRO

PIO

ROSI

0

-10

-20

Reduction

over

6 months (%)

-30

-39

-43

-40

P < 0.0001

-50

P < 0.0001

-54

-50

P < 0.0001

P = 0.03

-60

Neointimalarea

Neointimalarea

Neointimalarea

Restenosis

Endpoint

TZDs consistently reduce restenosis after coronary stenting in patients with diabetes

* vs diet

† vs other anti-diabetic therapy

TRO = troglitazone ROSI = rosiglitazone

PIO = pioglitazone

Takagi T et al. J Am Coll Cardiol 2000; Takagi T et al. Am J Cardiol 2002;

Takagi T et al. Am Heart J 2003; Choi D et al. Diabetes Care 2004.


Summary of effects of PPAR agonists on endothelial dysfunction in diabetes

  • Stimulates EC Nitric Oxide Release

  • Ameliorates EC Activation

  • Attenuates the Glucose-DAG-PKCb pathway

  • Clinical studies in diabetic & nondiabetic patients

  • Affects contractile, inflammatory & thrombotic dimensions of endothelial dysfunction


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