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Pleiotropic effects of glitazones: a double edge sword?

Salomone S - Front Pharmacol (2011)

Bottom Line: 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.Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biomedicine, Catania University Catania, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: While studying vasomotor effects of telmisartan (Siarkos et al., 2011), an angiotensin receptor antagonist endowed with PPARγ agonistic activity (Schupp et al., 2004), we recently made the serendipitous observation that, in vitro, troglitazone rapidly and reversibly blocks contraction of vascular smooth muscle induced by either K+-dependent depolarization or α1-adrenoceptor stimulation (Figure 3). Because this effect of troglitazone occurred already after only 30 min incubation, it does not seem to be consistent with the latency of PPARγ-activated gene expression, which requires at least 2 h for significantly changing mRNAs (Sears et al., 2007). Furthermore, troglitazone-induced block of vasoconstriction was rapidly reversible, upon just 30 min wash out, which again makes unlikely PPARγ stimulation as the underlying mechanism, because reversibility would imply longer time related to the turnover of PPARγ-induced mRNAs and proteins; finally, the lack of effect of 30 μM GW9662, a PPARγ antagonist (Han et al., 2001) that we used at a concentration much higher than the reported IC50 (3.8 nM, Seimandi et al., 2005), rules out the involvement of PPARγ. At first sight, the concentration of troglitazone used in the present experiment, 30 μM, may look too high (“too” implying a plethora of potential non-specific effects); it is not that high, however, when considering that, in vitro, PPARγ stimulation by troglitazone is often tested at 20 μM (Rogue et al., 2010) and that in humans, troglitazone Cmax is 1.5 μg/ml (corresponding to about 3 μM), following therapeutic 400 mg/day regimen (Loi et al., 1997). This preliminary observation, presently limited to just one glitazone, needs further investigation with other molecules of the class. Because this PPARγ-independent mechanism is likely to impact vascular tone in vivo, if confirmed with other therapeutically exploitable glitazones, such as pioglitazone, may have clinical significance in patients with type 2 diabetes, who are at high cardiovascular risk and/or have already developed cardiovascular diseases.


Pleiotropic effects of glitazones: a double edge sword?

Salomone S - Front Pharmacol (2011)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108480&req=5

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.
Mentions: While studying vasomotor effects of telmisartan (Siarkos et al., 2011), an angiotensin receptor antagonist endowed with PPARγ agonistic activity (Schupp et al., 2004), we recently made the serendipitous observation that, in vitro, troglitazone rapidly and reversibly blocks contraction of vascular smooth muscle induced by either K+-dependent depolarization or α1-adrenoceptor stimulation (Figure 3). Because this effect of troglitazone occurred already after only 30 min incubation, it does not seem to be consistent with the latency of PPARγ-activated gene expression, which requires at least 2 h for significantly changing mRNAs (Sears et al., 2007). Furthermore, troglitazone-induced block of vasoconstriction was rapidly reversible, upon just 30 min wash out, which again makes unlikely PPARγ stimulation as the underlying mechanism, because reversibility would imply longer time related to the turnover of PPARγ-induced mRNAs and proteins; finally, the lack of effect of 30 μM GW9662, a PPARγ antagonist (Han et al., 2001) that we used at a concentration much higher than the reported IC50 (3.8 nM, Seimandi et al., 2005), rules out the involvement of PPARγ. At first sight, the concentration of troglitazone used in the present experiment, 30 μM, may look too high (“too” implying a plethora of potential non-specific effects); it is not that high, however, when considering that, in vitro, PPARγ stimulation by troglitazone is often tested at 20 μM (Rogue et al., 2010) and that in humans, troglitazone Cmax is 1.5 μg/ml (corresponding to about 3 μM), following therapeutic 400 mg/day regimen (Loi et al., 1997). This preliminary observation, presently limited to just one glitazone, needs further investigation with other molecules of the class. Because this PPARγ-independent mechanism is likely to impact vascular tone in vivo, if confirmed with other therapeutically exploitable glitazones, such as pioglitazone, may have clinical significance in patients with type 2 diabetes, who are at high cardiovascular risk and/or have already developed cardiovascular diseases.

Bottom Line: 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.Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biomedicine, Catania University Catania, Italy.

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.

No MeSH data available.


Related in: MedlinePlus