Regulator of calcineurin 1 modulates vascular contractility and stiffness through the upregulation of COX-2-derived prostanoids. (July 2018)

• Record Type: Journal Article
• Authors: García-Redondo, Ana B.; Esteban, Vanesa; Briones, Ana M.; Díaz del Campo, Lucía S.; González-Amor, María; Méndez-Barbero, Nerea; Campanero, Miguel R.; Redondo, Juan M.; Salaices, Mercedes
• Is Part Of: Pharmacological research. Volume 133(2018)
• Page Start: 236
• Page End: 249
• Publication Date: 2018-07
• Subjects: Cn calcineurin -- COX-2 cyclooxygenase-2 -- KHS Krebs Henseleit Solution -- NO nitric oxide -- Rcan1 Regulator of calcineurin 1 -- ROS reactive oxygen species -- SMA small mesenteric arteries -- TXA2 thromboxane A2 -- VSMC vascular smooth muscle cells; Rcan1 -- COX-2 -- Vascular function and stiffness; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.01.001
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Cyclooxygenase-2 (COX-2) derived-prostanoids participate in the altered vascular function and mechanical properties in cardiovascular diseases. We investigated whether regulator of calcineurin 1 (Rcan1) participates in vascular contractility and stiffness through the regulation of COX-2. For this, wild type ( Rcan1 +/+ ) and Rcan1 -deficient ( Rcan1 −/− ) mice untreated or treated with the COX-2 inhibitor rofecoxib were used. Vascular function and structure were analysed by myography. COX-2 and phospo-p65 expression were studied by western blotting and immunohistochemistry and TXA2 production by ELISA. We found that Rcan1 deficiency increases COX-2 and IL-6 expression and NF-κB activation in arteries and vascular smooth muscle cells (VSMC). Adenoviral-mediated re-expression of Rcan1.4 in Rcan1 −/− VSMC normalized COX-2 expression. Phenylephrine-induced vasoconstrictor responses were greater in aorta from Rcan1 −/− compared to Rcan1 +/+ mice. This increased response were diminished by etoricoxib, furegrelate, SQ 29548, cyclosporine A and parthenolide, inhibitors of COX-2, TXA2 synthase, TP receptors, calcineurin and NF-κB, respectively. Endothelial removal and NOS inhibition increased phenylephrine responses only in Rcan1 +/+ mice. TXA2 levels were greater in Rcan1 −/− mice. In small mesenteric arteries, vascular function and structure were similar in both groups of mice; however, vessels from Rcan1 −/− mice displayed an increase in vascular stiffness that was diminished by rofecoxib. In conclusion, our results suggest that Rcan1 might act as endogenous negative modulator of COX-2 expression and activity by inhibiting calcineurin and NF-kB pathways to maintain normal contractility and vascular stiffness in aorta and small mesenteric arteries, respectively. Our results uncover a new role for Rcan1 in vascular contractility and mechanical properties.