Figueira Leticia, Israel Anita
School of Pharmacy, Laboratory of Neuropeptides, Universidad Central de Venezuela, Santa Rosa de Lima, Sec. Las Mesetas, Calle La Cima, Res. Mara, No. 82., Caracas, Venezuela.
School of Bioanalysis, Laboratory of Investigation and Postgraduate of School of Bioanalysis (LIPEB), School of Health Sciences, Universidad de Carabobo, Valencia, Carabobo, Venezuela.
J Mol Neurosci. 2017 Aug;62(3-4):281-290. doi: 10.1007/s12031-017-0936-7. Epub 2017 Jun 26.
Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM activates three different receptors, the AM type 1 (AM1), type 2 (AM2), and calcitonin gene-related peptide 1 (CGRP1) receptors. AM triggers several signaling pathways such as adenylyl cyclase (AC), guanylyl cyclase (GC), and extracellular signal-regulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. Cerebellar AM, AM-binding sites, and its receptor components are altered during hypertension, although it is unknown if these alterations are associated with changes in AM signaling. Thus, we assessed AM signaling pathways in cerebellar vermis of 16-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Animals were sacrificed by decapitation, and cerebellar vermis was microdissected under stereomicroscopic control. Tissue was stimulated in vitro with AM. Then the production of cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and cyclic adenosine monophosphate (cAMP) were assessed along with ERK1/2 activation and three antioxidant enzymes' activity: glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Our findings demonstrate that in the cerebellar vermis of normotensive rats, AM increases cGMP, NO, cAMP production, and ERK1/2 phosphorylation, while decreases basal antioxidant enzyme activity. In addition, AM antagonizes angiotensin II (ANG II)-induced increment of antioxidant enzyme activity. Hypertension blunts AM-induced cGMP and NO production and AM-induced decrease of antioxidant enzyme activity. Meanwhile, AM-induced effects on cAMP production, ERK1/2 activation, and AM-ANG II antagonism were not altered in SHR rats. Our results support a dysregulation of several AM signaling pathways during hypertension in cerebellar vermis.
肾上腺髓质素（AM）是一种参与血压调节的肽。AM激活三种不同的受体，即AM1型、AM2型和降钙素基因相关肽1（CGRP1）受体。AM触发多种信号通路，如腺苷酸环化酶（AC）、鸟苷酸环化酶（GC）和细胞外信号调节激酶（ERK），并调节活性氧（ROS）代谢。尽管尚不清楚这些改变是否与AM信号的变化有关，但在高血压期间小脑的AM、AM结合位点及其受体成分会发生改变。因此，我们评估了16周龄Wistar Kyoto（WKY）大鼠和自发性高血压大鼠（SHR）小脑蚓部的AM信号通路。通过断头处死动物，并在体视显微镜控制下显微解剖小脑蚓部。用AM在体外刺激组织。然后评估环磷酸鸟苷（cGMP）、一氧化氮（NO）和环磷酸腺苷（cAMP）的产生，以及ERK1/2激活和三种抗氧化酶的活性：谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）和超氧化物歧化酶（SOD）。我们的研究结果表明，在正常血压大鼠的小脑蚓部，AM可增加cGMP、NO、cAMP的产生以及ERK1/2磷酸化，同时降低基础抗氧化酶活性。此外，AM可拮抗血管紧张素II（ANG II）诱导的抗氧化酶活性增加。高血压会减弱AM诱导的cGMP和NO产生以及AM诱导的抗氧化酶活性降低。同时，AM对cAMP产生、ERK1/2激活以及AM-ANG II拮抗作用的影响在SHR大鼠中未改变。我们的结果支持高血压期间小脑蚓部几种AM信号通路的失调。
