1 / 16

New perspectives in the therapy with PPAR- γ agonists .

XIII International Symposium Heart Failure & Co. New perspectives in the therapy with PPAR- γ agonists. Carlo Maria Rotella, Ilaria Dicembrini. Napoli, 12-13 aprile 2013. Properties of PPAR- γ. PPAR- γ ligands. Adverse events associated with PPAR- γ agonists.

farren
Download Presentation

New perspectives in the therapy with PPAR- γ agonists .

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related