New perspectives in the therapy with

PPAR-γ agonists.

Carlo Maria Rotella, Ilaria Dicembrini

Napoli, 12-13 aprile 2013

XIII International Symposium Heart Failure & Co.

Properties of PPAR-γ

PPAR-γ ligands

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

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

Pioglitazone like a partial PPAR-α agonist in vitro

PPAR- γ independent mechanisms:Cardiomycocytes protective effects induced by

Pioglitazone

PPAR- α dependent mechanisms:Cardiomycocytes protective effects

induced by PioglitazonePioglitazone 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.

Pioglitazone-treated animalsControl animals

Hippocampus

Temporal Cortex

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.

Pioglitazone and Bladder cancer

PPAR-γ ligands & Cancer

1. Cell growth and proliferation

2. Inflammatory pathways

3. TGF-β pathway

EMT= epithelial mesenchymal transition

A.K. Reka et al. Lung Cancer 72 (2011) 154–159

4. Prevent cytoxicity induced by platinum drugs, 5. Synergy with cisplatin and paclitaxel, 6. Facilitation of the epidermal growth factor receptor signaling (gefitinib), 7.Potentiation of HDAC inhibitor (phenylbutirate)

PPAR-γ ligands & Cancer

A.K. Reka et al. Lung Cancer 72 (2011) 154–159

PPAR-γ agonists & Cancer

Retrospective analysis of more than 80.000 TZD users compared to nonusers after adjusting for confounding variables:

33% reduction in lung cancer risk.

Conclusions