Pleiotropic effects of glitazones: a double edge sword?

Abstract

Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

Keywords: glitazones; pioglitazone; rosiglitazone; troglitazone; vascular tone.

Figure 1

Chemical structures of glitazones (A) and glitazars (B). The chemical structure shared by all the compounds of the class is indicated in green, while in red is the part of the molecule that characterizes individual compounds.

Figure 2

Scheme of PPARγ activation and signaling. (A) In the absence of ligand, PPARγ is bound to co-repressors and may interact with DNA in a manner that prevent transcription. (B) Upon binding the ligand, PPARγ undergoes conformational changes inducing the recruitment of specific co-activators and allowing hetero-dimerization with retinoid receptors. These multimeric complex activates transcriptional activity and gene expression. L, ligand; RXR, retinoid receptor; LBD, ligand binding domain; DBD, DNA binding domain; PPRE, PPAR responsive element; SRC-1, steroid receptor co-activator-1; HAT, histone acetyl transferase.

Figure 3

Effect of troglitazone on vasomotor responses to phenylephrine (PE) in isolated femoral arteries. Arterial segments, mounted in a wire myograph, were first challenged with a 100-mM K⁺ depolarizing solution, then with cumulative concentrations of PE (10 nM–10 μM), added to the organ chamber by half log increase, as indicated by dots on the tracing. Three consecutive runs of vasoconstriction to PE were carried out in each preparation, interrupted by 30-min wash out intervals. Upper trace (A) shows three reproducible concentration–contraction curves in a control preparation; middle trace (B) shows a block of vasoconstriction to PE, following incubation with troglitazone, that is reversed in runs 2 and 3, following troglitazone wash out; lower trace (C) shows block of vasoconstriction to PE by troglitazone, unaffected by preincubation with GW9662, a PPAR antagonist.