Abstract
The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects in the cell although there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone. Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes in contraction and dilation measured. Our data shows that the PPARβ/δ agonist GW0742 (10-7M) inhibits contractile responses to U46619 and phenylephrine, and that these responses are similar in normal and Streptozotocin (STZ) diabetic rat aorta. ROCK inhibitors Fasudil and Y27632 significantly reduced GW0742 mediated dilation of naïve rat aorta, but Fasudil had no effect on GW0742 dilation in STZ diabetic rat aorta. In contrast, STZ diabetic rat aorta pre-contracted with high [K+] Krebs lacked a dilatory response to GW0742, which taken together indicates that the mechanism of action of GW0742 mediated dilation changes in the diabetic state compared to non-diabetic state. This is the first direct evidence demonstrating the non- PPARβ/δ effect of GW0742 on contraction is irrespective to the diabetic state, and that GW0742 has the potential to induce vasodilation via multiple off-target mechanisms.
Highlights
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily
Direct activation of PPARβ/δ with agonist GW0742 in rats treated with Streptozotocin (STZ; a model of Type I diabetes) improves insulin signaling [5] and glucose homeostasis [6]
Our results demonstrate that GW0742 inhibits contraction of aorta from naïve and STZ Type 1 diabetic rat, and that GW0742 induces vasodilation mediated in part by the RhoA/Rho associated protein kinase (ROCK) pathway in naïve rat aortas and potassium channels in STZ diabetic rat aortas
Summary
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Signaling via PPARβ/δ has a number of effects on cell function, including lipid metabolism [1], glucose metabolism [2], insulin sensitivity [2], and inflammation [3]. There are complex mechanisms by which PPARβ/δ controls gene transcription through induction and transrepression of other nuclear receptors which are yet to be fully defined [4]. Direct activation of PPARβ/δ with agonist GW0742 (a close mimetic of GW501516) in rats treated with Streptozotocin (STZ; a model of Type I diabetes) improves insulin signaling [5] and glucose homeostasis [6]. The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects in the cell there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone.
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