Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Cardiovasculares, Spain.
Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Departamento de Inmunología, Instituto de Investigación Fundación Jiménez Díaz, Madrid, Spain.
Pharmacol Res. 2018 Jul;133:236-249. doi: 10.1016/j.phrs.2018.01.001. Epub 2018 Jan 5.
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 TXA 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, TXA synthase, TP receptors, calcineurin and NF-κB, respectively. Endothelial removal and NOS inhibition increased phenylephrine responses only in Rcan1 mice. TXA 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.
环氧化酶-2（COX-2）衍生的前列腺素参与心血管疾病中血管功能和机械特性的改变。我们研究了钙调神经磷酸酶 1（Rcan1）是否通过调节 COX-2 参与血管收缩性和僵硬。为此，使用了野生型（Rcan1）和 Rcan1 缺陷型（Rcan1）小鼠，未经处理或用 COX-2 抑制剂罗非昔布处理。通过肌动描记法分析血管功能和结构。通过 Western 印迹和免疫组织化学研究 COX-2 和磷酸化 p65 的表达，通过 ELISA 研究 TXA 的产生。我们发现 Rcan1 缺乏增加了动脉和血管平滑肌细胞（VSMC）中的 COX-2 和 IL-6 表达和 NF-κB 激活。Rcan1 VSMC 中的腺病毒介导的 Rcan1.4 再表达使 COX-2 表达正常化。与 Rcan1 相比，Rcan1 小鼠主动脉中对苯肾上腺素诱导的血管收缩反应更大。这种增加的反应分别被 COX-2、TXA 合酶、TP 受体、钙调神经磷酸酶和 NF-κB 的抑制剂罗非昔布、非甾体类抗炎药、SQS29548、环孢菌素 A 和小白菊内酯减弱。内皮去除和 NOS 抑制仅在 Rcan1 小鼠中增加了苯肾上腺素的反应。Rcan1 小鼠中的 TXA 水平更高。在小肠系膜动脉中，两组小鼠的血管功能和结构相似；然而，来自 Rcan1 小鼠的血管显示出血管僵硬增加，罗非昔布可减轻这种增加。总之，我们的结果表明，Rcan1 可能通过抑制钙调神经磷酸酶和 NF-kB 途径作为 COX-2 表达和活性的内源性负调节剂，分别维持主动脉和小肠系膜动脉的正常收缩性和血管僵硬。我们的结果揭示了 Rcan1 在血管收缩性和机械特性中的新作用。
