Adrenomedullin inhibits angiotensin II-induced contraction in human aortic smooth muscle cells

Rossi, Fábio; Zappa, Catia; Ferraresi, Antonella; Santiemma, V.

doi:10.1016/j.regpep.2005.09.029

Cited by 10 publications

(4 citation statements)

References 24 publications

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“…PI-3K and Akt proteins are expressed constitutively in cultured vascular smooth muscle cells (VSMCs). Activated Akt has been found in vascular remodeling after vascular injury accompanied by VSMC proliferation [46]. Activation of Akt is tightly coupled to proliferation of VSMCs involved in vascular remodeling [47].…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

et al. 2014

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Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

et al. 2014

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“…Several signaling pathways have been described through which ADM causes vasodilation, both endothelium dependent and endothelium independent ( 55 ), which are depicted in Figure 1 . In an endothelium-independent way, binding of ADM with its receptors on VSMCs increases intracellular cyclic adenosine monophosphate (cAMP) ( 63 , 64 ), which subsequently activates protein kinase A (PKA, also known as cAMP-dependent kinase) ( 42 ). PKA inhibits smooth muscle cell contraction in several ways.…”

Section: The Role Of Adm In the Regulation Of Blood Pressurementioning

confidence: 99%

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Geven

Kox²,

Pickkers³

2018

Front. Immunol.

106

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Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.

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“…In addition, in human aorta smooth muscle cells, AM inhibited in a dose-dependent manner, ANG II induced-contraction and proliferation; and a stimulatory effect on proliferation of quiescent cells. The cAMP/PKA pathway was involved in the AM inhibitory effect of ANG II-induced proliferation [46]. Furthermore, AM decreased ANG II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of extracellular matrix-related genes in rats.…”

Section: Antagonism Between Adrenomedullin and Angiotensin II In Cerementioning

confidence: 93%

Adrenomedullin and Angiotensin II in Rat Cerebellar Vermis: Reactive Oxygen Species Production

Figueira¹,

Israel²

2017

Foc Sci

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Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM exerts its effects through the activation of three 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), extracellular signalregulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. In brain, AM and their receptors are expressed in several localized areas, including the cerebellum. AM has been reported as an antioxidant. Recent evidence suggests the presence of an adrenomedullinergic and angiotensinergic system of physiological relevance in cerebellum vermis. To establish the role of AM in the regulation of cerebellar ROS metabolism, it was assessed the effect of AM and angiotensin II (ANG II) on three antioxidant enzymes activity: catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), and on thiobarbituric acid reactive substances (TBARS) production in rat cerebellar vermis. The findings demonstrated that in cerebellar vermis, AM decreased and ANG II increased CAT, GPx and SOD activity and TBARS production. Likewise, AM antagonized ANG II-induced increase antioxidant enzyme activity. AM(22-50) and CGRP(8-37) blunted AM-induced decrease of antioxidant enzymes activity and TBARS production indicating that these actions are mediated through AM and CGRP1 receptors. Further, PKA inhibitor (PKAi) blunted AM action whilst apocynin and chelerythrine reverted ANG II action, suggesting that AM antioxidant action is mediated through stimulation of protein kinase A (PKA) activity, while ANG II stimulation occurs through protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase (PKC/NAD(P)H oxidase) pathway. These results support the role of AM in the regulation of cerebellar antioxidant enzymes activity and suggest a physiological role for AM in cerebellum.

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Adrenomedullin inhibits angiotensin II-induced contraction in human aortic smooth muscle cells

Cited by 10 publications

References 24 publications

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Adrenomedullin and Angiotensin II in Rat Cerebellar Vermis: Reactive Oxygen Species Production

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