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New perspectives in cardio protection: Focus on PPAR  activation

This article explores the role of PPARγ activation in cardioprotection, focusing on its effects on insulin resistance, glucose uptake, glucose absorption, and hepatic glucose output. It also discusses the potential benefits of PPARγ agonists in the treatment of obesity, diabetes, and atherosclerosis.

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New perspectives in cardio protection: Focus on PPAR  activation

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  1. New perspectives in cardio protection: Focus on PPAR activation

  2. α-Glucosidase inhibitors Thiazolidinediones Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake Intestine: ↓glucose absorption Blood glucose Liver: ↓hepatic glucose output ↑glucose uptake Pancreas: ↑insulin secretion Sulfonylureas and repaglinide Principal mechanisms of action for oral diabetic agents Biguanides Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411

  3. Site of action MoA Agents SulphonylureasOther insulinsecretagogues Insulinsecretion BiguanidesThiazolidinediones Glucoseproduction -glucosidaseinhibitors Slow carbohydratedigestion - Peripheral insulinsensitivity Thiazolidinediones(biguanides) Site and mode of action of oral antidiabetic medications DeFronzo RA. Ann Intern Med 1999;131:281-303

  4. 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. ArteriosclerThrombVasc Biol. 2006;26:28-40.

  5. PPARs: Overview Blaschke F et al. ArteriosclerThrombVasc Biol. 2006;26:28-40 Semple RK et al. J Clin Invest. 2006;116:581-9

  6. 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-αproduction  Adiponectin  Free fatty acids Inzucchi SE. JAMA. 2002;287:360-72

  7. 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 Lumen Lumen Necrotic core EC VSMC Monocytes Adapted from Marx N et al. ArteriosclerThrombVasc Biol. 1999;19:546-51

  8. – – – – PPAR activation and atherosclerosis: A hypothesis Ligand:Endogenous or synthetic Activated PPAR DirectVascular and inflammatory cells IndirectFat, liver, skeletal muscle cells Reducesinflammation  Cytokines  Chemokines Cholesterol efflux Adhesion molecules  FFA Glucose  Insulin sensitivity Triglycerides HDL Atherogenic LDL Blunts atherosclerosis Plutzky J. Science. 2003;302:406-7.

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