New perspectives in cardio protection: Focus on PPAR activation
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Transcript of New perspectives in cardio protection: Focus on PPAR activation
New perspectives in cardio protection:
Focus on PPAR activation
Principal mechanisms of action for oral diabetic agents
Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411
Biguanides
α-Glucosidase inhibitors
Intestine: ↓glucose absorption
Liver: ↓hepatic glucose output
↑glucose uptake
Blood glucose
Sulfonylureas and repaglinide
Pancreas: ↑insulin secretion
Muscle and adipose tissue: ↓insulin resistance
↑glucose uptake
Thiazolidinediones
Site and mode of action of oral antidiabetic medications
DeFronzo RA. Ann Intern Med 1999;131:281-303
MoA AgentsInsulin
secretionSulphonylureas
Other insulinsecretagogues
Glucoseproduction
BiguanidesThiazolidinediones
Slow carbohydratedigestion
--glucosidaseinhibitors
Peripheral insulinsensitivity
Thiazolidinediones(biguanides)
Site of action
Peroxisome proliferator-activator receptors (PPARs)
PPAR , , and belong to the nuclear hormone receptor superfamily
PPAR agonists appear to play a critical role in regulating
inflammation, lipoprotein metabolism, and glucose homeostasis
Studies suggest that PPAR agonists exert antiatherogenic effects by inhibiting proinflammatory gene expression and enhancing cholesterol efflux
PPAR agonists have potential in the treatment of obesity, diabetes, and atherosclerosis
Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.
PPARs: OverviewPPAR
receptor Main tissue location Regulates
Alpha
Liver, skeletal muscle, heart, kidney
Lipid metabolism (dyslipidemia)Inflammation/atherosclerosis
Gamma
Fat cells, macrophages
Insulin sensitivity/glucose metabolismInflammation/atherosclerosisAdipocyte differentiation
Delta
Widespread, includingskeletal muscle andfat cells
Fatty acid oxidationInflammation
Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40Semple RK et al. J Clin Invest. 2006;116:581-9
Focus on PPAR activation
• Reduces insulin resistance
• Preserves pancreatic -cell function
• Improves CV risk profile
Improves dyslipidemia ( HDL, LDL density, or TG)
Renal microalbumin excretion
Blood pressure
VSMC proliferation/migration in arterial wall
PAI-1 levels
C-reactive protein levels
TNF-α production
Adiponectin
Free fatty acids
Inzucchi SE. JAMA. 2002;287:360-72
Beyond fat and glucose: Potential for CV benefits with PPAR agonists
PPAR is expressed incell types associated with CV disease:
– Vascular endothelial cells (EC)
– Vascular smooth muscle cells (VSMC)
– T-lymphocytes
– Monocyte/macrophages
– Cardiac myocytes
– Renal tubule cells Monocytes
Necrotic core
Lumen
VSMC
Adapted from Marx N et al. Arterioscler Thromb Vasc Biol. 1999;19:546-51
Lumen
EC
PPAR activation and atherosclerosis: A hypothesis
Plutzky J. Science. 2003;302:406-7.
Blunts atherosclerosis
IndirectFat, liver, skeletal muscle cells
Ligand:Endogenousor synthetic
Activated PPAR
Reducesinflammation
DirectVascular and inflammatory cells
FFA Glucose Insulin sensitivity Triglycerides HDL Atherogenic LDL
Cytokines Chemokines Cholesterol efflux Adhesion molecules
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