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Novel Insights into PPAR-γ Agonists Therapy for Heart Failure

Discover the properties of PPAR-γ, related adverse events, and therapeutic potential in heart failure. Explore insights on weight gain, bone fractures, cardiovascular risk, and protective effects on cardiomycocytes. Uncover how PPAR-γ agonists affect cancer pathways and show promise in cancer prevention and treatment. Delve into the impact on sepsis and bladder cancer, with a retrospective lung cancer risk analysis.

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Novel Insights into PPAR-γ Agonists Therapy for Heart Failure

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  1. XIII International Symposium Heart Failure & Co. New perspectives in the therapy withPPAR-γagonists. Carlo Maria Rotella, Ilaria Dicembrini Napoli, 12-13 aprile 2013

  2. Properties of PPAR-γ

  3. PPAR-γ ligands

  4. Adverse events associated with PPAR-γ agonists • Chronic heart failure/oedema and fluid retention Increasing sodium retention and plasma volume expansion due to PPAR-γ in the epithelium of the renal collecting ducts Act synergistically with insulin to increase sympathetic nervous activity, which causes arterial vasodilation leading to sodium retention Change in endothelial permeability leading to extracellular fluid increase Similarity in thiazolidinediones to the dihyrdopyridine type of calcium-channel blockers, which exert their effect through L-type calcium channels and cause increased fluid permeability • Weight gain Redistribution of fat from central to peripheral sites Adipocyte hyperplasia, fluid retention and decreased glycosuria Genetic factors • Bone fractures Associated with a loss of bone density Decreased osteoblast differentiation: PPAR-γ signals preferential differentiation of mesenchymal cells to adipocytes rather than osteoblasts, thereby reducing bone formation and mass Increased osteoclast formation

  5. Reported meta-analysis about the effct of TZD on cardiovascular risk in type 2 Diabetes

  6. Pioglitazone like a partial PPAR-α agonist in vitro

  7. PPAR- γ independent mechanisms:Cardiomycocytes protective effects induced by Pioglitazone

  8. PPAR- α dependent mechanisms:Cardiomycocytes protective effects induced by Pioglitazone Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-γ-independent manner. Basic Res Cardiol. 2011;106(3):431-46.

  9. Control animals Pioglitazone-treated animals Hippocampus Temporal Cortex

  10. PPAR-γ ligands & Sepsis On a mouse model of sepsis induced by a bacterial endotoxin , PPAR-γ like a anti-inflammatory mediator by inhibiting early and late proinflammatory cytokines such as TNF-α, IL-6, iNOS, and HMGB1.

  11. Pioglitazone and Bladder cancer

  12. PPAR-γ ligands & Cancer 1. Cellgrowth and proliferation 3. TGF-βpathway 2. Inflammatorypathways EMT= epithelial mesenchymal transition A.K. Reka et al. Lung Cancer 72 (2011) 154–159

  13. PPAR-γ ligands & Cancer 4. Preventcytoxicityinducedbyplatinumdrugs, 5. Synergywithcisplatin and paclitaxel, 6. Facilitationof the epidermalgrowthfactorreceptorsignaling (gefitinib), 7.Potentiation of HDAC inhibitor (phenylbutirate) A.K. Reka et al. Lung Cancer 72 (2011) 154–159

  14. PPAR-γ agonists & Cancer Retrospectiveanalysisof more than 80.000 TZD userscomparedtononusersafteradjustingforconfoundingvariables: 33% reduction in lungcancerrisk.

  15. Conclusions

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