Irisin relaxes rat thoracic aorta: MEK1/2 signaling pathway, [K.sub.V] channels, [SK.sub.Ca] channels, and [BK.sub.Ca] channels are involved in irisin-induced vasodilation

This study investigated the effects of irisin on vascular smooth muscle contractility in rat thoracic aorta, and the hypothesis that mitogen-activated protein kinase kinase (MEK1/2) signaling pathway, voltage-gated potassium ([K.sub.V]) channels, small-conductance calcium-activated potassium ([SK.sub.Ca]) channels, and large-conductance calcium-activated potassium ([BK.sub.Ca]) channels may have roles in these effects. Isometric contraction-relaxation responses of isolated thoracic aorta rings were measured with an organ bath model. The steady contraction was induced with [10.sup.-5] M phenylephrine (PHE), and then the concentration-dependent responses of irisin ([10.sup.-9] - [10.sup.-6] M) were examined in endothelium-intact and - denuded rat thoracic aortas. Also, the effects of irisin incubations on PHE-mediated contraction and acetylcholine (ACh)--mediated relaxation were studied. Irisin exerted the vasorelaxant effects in both endothelium-intact and -denuded aortic rings at concentrations of [10.sup.-8], [10.sup.-7], and [10.sup.-6] M compared with the control groups (p < 0.001). Besides, pre-incubation of aortic rings with irisin (10 nM, 100 nM, or 1 [micro]M for 30 min) augmented ACh-mediated ([10.sup.9] - [10.sup.5]) vasodilation in PHE-precontracted thoracic aorta segments but did not modulate PHE-mediated ([10.sup.9] - [10.sup.5]) contraction. In addition, MEK1/2 inhibitor U0126, [K.sub.V] channel blocker XE-991, [SK.sub.Ca] channel blocker apamin, and [BK.sub.Ca] channel blocker tetraethylammonium (TEA) incubations significantly inhibited the irisin-induced relaxation responses. In conclusion, the first physiological findings were obtained regarding the functional relaxing effects of irisin in rat thoracic aorta. The findings demonstrated that irisin induces relaxation responses in endothelium-intact and (or) endothelium-denuded aortic rings in a concentration-dependent manner. Furthermore, this study is the first to report that irisin-induced relaxation responses are related to the activity of the MEK1/2 pathway, [K.sub.V] channels, and calcium-activated [K.sup.+] ([SK.sub.Ca] and [BK.sub.Ca]) channels. Key words: irisin, rat thoracic aorta, vasodilation, mitogen-activated protein kinase kinase, potassium channels. Cette etude portait sur les effets de l'irisine sur la contractilite du muscle lisse vasculaire dans l'aorte thoracique de rat, avec pour hypothese que la voie de signalisation de la MEK1/2 (pour << mitogen-activated protein kinase kinase >>), les canaux potassiques dependants du voltage ([K.sub.V]), les canaux potassiques a faible conductance actives par le calcium ([SK.sub.Ca]) et les canaux potassiques a conductance elevee actives par le calcium ([BK.sub.Ca]) peuvent jouer un role dans ces effets. Nous avons mesure la contraction et la relaxation isometriques dans des anneaux isoles d'aorte thoracique en bain d'organe. Nous avons obtenu la contraction stable a l'aide de phenylephrine (PHE) a [10.sup.-5] M, puis examine les reactions dependantes des concentrations d'irisine ([10.sup.-9] - [10.sup.-6] M) dans des aortes thoraciques de rats denudees et dont l'endothelium etait intact. Nous avons aussi etudie les effets de l'incubation en presence d'irisine sur la contraction mediee par la PHE et la relaxation mediee par l'acetylcholine (ACh). Dans les anneaux dont l'endothelium etait intact comme denudes, l'irisine entrainait des effets vasorelaxants plus marques que chez les temoins a des concentrations de [10.sup.-8], de [10.sup.-7] et de [10.sup.-6] M (p < 0,001). Par ailleurs, l'incubation prealable des anneaux aortiques en presence d'irisine (10 nM, 100 nM ou 1 [micro]M pendant 30 minutes) entrainait une augmentation de la vasodilatation mediee par l'ACh ([10.sup.9] - [10.sup.5]) dans les segments d'aorte thoracique precontractes a l'aide de PHE, mais sans modulation de la contraction mediee par la PHE ([10.sup.9] - [10.sup.5]). De plus, l'incubation en presence de U0126 (un inhibiteur de la MEK1/2), de XE-991 (un bloqueur des canaux [K.sub.V]), d'apamine (un bloqueur des canaux [SK.sub.Ca]) et de tetraethylammonium (ou TEA, un bloqueur des canaux [BK.sub.Ca]) entrainait une inhibition marquee de la relaxation entrainee par l'irisine. En conclusion, nous avons obtenu les premiers resultats physiologiques quant a la relaxation fonctionnelle entrainee par l'irisine dans l'aorte thoracique chez le rat. Les resultats ont montre avec des anneaux aortiques denudes et/ou dont l'endothelium etait intact que l'irisine entraine des relaxations proportionnelles a la concentration. En outre, il s'agit de la premiere etude qui rapporte que les relaxations entrainees par l'irisine sont liees a l'activite de la voie de signalisation de la MEK1/2, des canaux [K.sub.V] et des canaux [K.sub.+] actives par le calcium ([SK.sub.Ca] et [BK.sub.Ca]). [Traduit par la Redaction] Mots-cles : irisine, aorte thoracique de rat, vasodilatation, MEK1/2, canaux potassiques.
1. Introduction Irisin, a newly identified hormone containing 112 amino acids that is secreted mainly by skeletal muscle cells during exercise, is a cleavage product of fibronectin type III domain-containing [...]