Differential sensitivities of the vascular KATP channel to various PPAR activators

Abstract

Several agonists of the peroxisome proliferator-activated receptors (PPARs) are currently used for the treatment of metabolic disorders including diabetes. We have recently shown that one of them, Rosiglitazone, inhibits the vascular ATP-sensitive K+ (KATP) channel and compromises the coronary vasodilation by the β-adrenoceptor agonist. Here, we show evidence for the channel inhibition by various PPAR agonists, information that may be useful for finding new therapeutical agents with less cardiovascular side-effects and more selective KATP channel blockers targeting at the Kir6.1 subunit. Structural comparison of these PPAR agonists may shed insight into the critical chemical groups for the channel inhibition. Kir6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell voltage clamp. The Kir6.1/SUR2B channel was strongly inhibited by several PPARγ agonists with potencies similar to, or higher than, that of Rosiglitazone, while other PPARγ agonists barely inhibited the channel. The Kir6.1/SUR2B channel was also inhibited by PPARα and PPARβ/δ agonists with intermediate potencies. The structure necessary for the channel inhibition appears to include the thiazole linked to an aromatic or furan ring. Additions of side groups such as small aliphatic chain increased the potency for channel inhibition, while additions of aromatic rings reduced it. These results indicate that the PPARγ agonists with weak KATP channel inhibition may be potential candidates as therapeutical agents, and those with strong channel inhibition may be used as selective KATP channel blockers. The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects.

The Non-Genomic Effects of the PPARβγ Agonist GW0742 on Streptozotocin Treated Rat Aorta

“…Studies have been conducted to determine the mechanisms by which the activated PPARβ/δ induces vasodilation in arteries, possibly mediated by direct interaction with RhoA [8,14], activation of PI3-Akt-eNOS pathways [15] or activation of K + channels [16]. In order to address the question as to whether PPARβ/δ directly interferes with the RhoA/ROCK pathway and K + channels, we took advantage of the dilatory properties of the agonist GW0742.…”

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

“…are another class of drugs used clinically for the treatment of type 2 diabetes via their effect on peroxisome proliferator-activated receptors (PPARs) [ 125 ]. However, patch clamp experiments on HEK cells expressing various subtypes of K ATP channels have shown that these compounds also block vascular K ATP channels to various degrees [ 130 ]. Rosiglitazone was found to inhibit all isoforms of K ATP channels.…”

Acting on Hormone Receptors with Minimal Side Effect on Cell Proliferation: A Timely Challenge Illustrated with GLP-1R and GPER

“…Recently, signaling engaged after GPCR recruitment of β-arrestin proteins have emerged as new G protein-independent intracellular signaling pathways (Luttrell and Gesty-Palmer, 2010; Rajagopal et al, 2010a). To increase the complexity, a single GPCR has pleiotropic signaling properties and each signal can crosstalk at different levels with the transactivation of cell surface receptor having tyrosine kinase activity (EGF-R, PDGF-R, FGF-R, for examples) or serine/threonine kinase activity (TGF-β, for example) or with the formation of multimers, thus potentially influencing the signaling pathways of the different receptors (Burch et al, 2012; Wang and Lewis, 2013). Indeed, numerous biochemical and biophysical studies supports that GPCRs can form physiologically relevant homo-, hetero-, or oligo-mers (Angers et al, 2002).…”