Soluble (pro)renin receptor: a novel ligand for angiotensin II type 1 receptor?

2021 ◽  
Vol 135 (13) ◽  
pp. 1627-1630
Author(s):  
Keiichi Torimoto ◽  
Satoru Eguchi
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Diet Induced Obesity ◽  
Prorenin Receptor ◽  
Umbilical Vein Endothelial Cells ◽  
First Time

Abstract This commentary highlights the study entitled ‘Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor’ presented by Fu et al. published in Clinical Science (Clin Sci (Lond) (2021) 135(6), https://doi.org/10.1042/CS20201047). The authors evaluated the role of the soluble (pro)renin receptor (sPRR), a cleavage product of the prorenin receptor (PRR) by the site 1 protease, as a ligand for angiotensin II type 1 receptor (AT1R). They presented for the first time that sPRR directly interacts with AT1R, causing nuclear factor-κB activation, inflammation, apoptosis, and endothelial dysfunction in primary human umbilical vein endothelial cells (HUVECs). Furthermore, the interaction between sPRR and AT1R was responsible for endothelial dysfunction and hypertension in diet-induced obesity mice. These results provide a potential mechanism for obesity-induced endothelial dysfunction and hypertension. Thus, the sPRR/AT1R complex may be a novel therapeutic target for cardiovascular diseases associated with endothelial dysfunction.

Abstract 110: Thrombospondin Type-1 Domain-Containing Protein 1 (THSD1), an Intracranial Aneurysm Susceptibility Gene, Mediates Cell Adhesion in Human Umbilical Vein Endothelial Cells

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Xiaoqian Fang ◽  
Dong H Kim ◽  
Teresa Santiago-Sim
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Focal Adhesion ◽  
Umbilical Vein ◽  
Adhesion Formation ◽  
Wild Type ◽  
Focal Adhesion Formation ◽  
Umbilical Vein Endothelial Cells

Introduction: An intracranial aneurysm (IA) is a weak spot in cerebral blood vessel wall that can lead to its abnormal bulging. Previously, we reported that mutations in THSD1 , encoding thrombospondin type-1 domain-containing protein 1, are associated with IA in a subset of patients. THSD1 is a transmembrane molecule with a thrombospondin type-1 repeat (TSR). Proteins with TSR domain have been implicated in a variety of processes including regulation of matrix organization, cell adhesion and migration. We have shown that in mouse brain Thsd1 is expressed in endothelial cells. Hypothesis: THSD1 plays an important role in maintaining the integrity of the endothelium by promoting adhesion of endothelial cells to the underlying basement membrane. Methods: Human umbilical vein endothelial cells are used to investigate the role of THSD1 in vitro . THSD1 expression was knocked-down by RNA interference. Cell adhesion assay was done on collagen I-coated plates and focal adhesion formation was visualized using immunofluorescence by paxillin and phosphorylated focal adhesion kinase (pFAK) staining. THSD1 re-expression is accomplished by transfection with a pCR3.1-THSD1-encoding plasmid. Results: Knockdown of THSD1 caused striking change in cell morphology and size. Compared to control siRNA-treated cells that exhibited typical cobblestone morphology, THSD1 knockdown cells were narrow and elongated, and were significantly smaller ( p <0.01). Cell adherence to collagen I-coated plates was also attenuated in THSD1 knockdown cells ( p <0.01). Consistent with this finding is the observation that the number and size of focal adhesions, based on paxillin and pFAK staining, were significantly reduced after THSD1 knockdown ( p <0.01). These defects in cell adhesion and focal adhesion formation were rescued by re-expression of wild type THSD1 ( p <0.05). In contrast, initial studies indicate that expression of mutated versions of THSD1 as seen in human patients (L5F, R450*, E466G, P639L) could not restore cell adhesion and focal adhesion formation to wild type levels. Conclusions: Our studies provide evidence for a role of THSD1 and THSD1 mutations in endothelial cell adhesion and suggest a possible mechanism underlying THSD1 -mediated aneurysm disease.

Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-α

2004 ◽  
Vol 286 (4) ◽  
pp. C779-C784 ◽  
Author(s):  
Ivan A. Arenas ◽  
Yi Xu ◽  
Patricio Lopez-Jaramillo ◽  
Sandra T. Davidge
Keyword(s):  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Vascular Disease ◽  
Neutralizing Antibodies ◽  
Umbilical Vein ◽  
Ang Ii ◽  
Tnf Α ◽  
Mrna And Protein Expression ◽  
Umbilical Vein Endothelial Cells

Angiotensin II (ANG II) has been etiologically linked to vascular disease; however, its role in the alterations of endothelial function that occur in vascular disorders is not completely understood. Matrix metalloproteinases (MMPs) and proinflammatory cytokines are involved in the pathological remodeling of blood vessels that occurs in vascular disease. In this study we evaluated the effects of ANG II on tumor necrosis factor (TNF)-α and MMP-2 production in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with ANG II (0.1–10 μM) for 24 h, in the presence or absence of antagonists of ANG II type 1 (AT1R) and type 2 (AT2R) receptors, and the production and release of TNF-α and MMP-2 were assessed. ANG II increased TNF-α mRNA and protein expression and the release of bioactive TNF-α. Moreover, ANG II induced MMP-2 release and reduced the secretion of tissue inhibitor of MMP (TIMP)-2 from endothelial cells. To elucidate whether endogenous TNF-α could mediate the effects of ANG II on MMP-2 release, cells were pretreated with anti-TNF-α neutralizing antibodies or pentoxifylline (an inhibitor of TNF-α synthesis). TNF-α inhibition prevented the secretion of MMP-2 induced by ANG II. Furthermore, AT1R antagonism with candesartan prevented the formation of MMP-2 and TNF-α and the reduction of TIMP-2 induced by ANG II. These results indicate that ANG II, via AT1R, modulates the secretion of TNF-α and MMP-2 from endothelial cells and that TNF-α mediates the effects of ANG II on MMP-2 release.

scholarly journals Selective recruitment of neutrophils and lymphocytes by thrombin: a role for NF-κB

2001 ◽  
Vol 281 (2) ◽  
pp. H784-H795 ◽  
Author(s):  
Jaswinder Kaur ◽  
Richard C. Woodman ◽  
Lena Ostrovsky ◽  
Paul Kubes
Keyword(s):  
De Novo ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Flow Chamber ◽  
Neutrophil Recruitment ◽  
Leukocyte Recruitment ◽  
Vascular Adhesion ◽  
Umbilical Vein Endothelial Cells ◽  
Factor Α

With the use of a whole blood laminar flow chamber system, we examined the types of leukocytes, adhesion molecules and the role of nuclear factor-κB (NF-κB) in thrombin-induced leukocyte recruitment. Primary human umbilical vein endothelial cells (HUVEC) stimulated with thrombin induced a significant increase in P-selectin-dependent neutrophil recruitment. Unexpectedly, brief thrombin stimulation (3 min) of endothelium also induced a significant lymphocyte recruitment 4 h later in addition to neutrophil recruitment. E-selectin antibody reduced neutrophil recruitment by >90%, whereas vascular adhesion molecule-1 (VCAM-1)/α4-integrin were primarily responsible for lymphocyte recruitment. To examine whether NF-κB contributed to leukocyte recruitment 4 h post thrombin stimulation, we treated HUVEC with the NF-κB inhibitor MG-132 for 1 h before thrombin stimulation. MG-132 significantly reduced the number of rolling (77.1%) and adherent (79.9%) leukocytes compared with thrombin stimulation alone. The inhibitor was more effective at preventing lymphocyte than neutrophil recruitment, consistent with its greater effect on VCAM-1 versus E-selectin expression. Tumor necrosis factor-α- and MG-132-treated HUVEC displayed no inhibition of leukocyte recruitment despite a decrease in NF-κB activation. In summary, thrombin causes predominant neutrophil recruitment via rapid P-selectin expression but also a delayed E-selectin- and VCAM-1-dependent neutrophil and lymphocyte recruitment via de novo protein synthesis. Although NF-κB mobilization was essential for thrombin-mediated VCAM-1-dependent recruitment, it only partially contributed to E-selectin-dependent recruitment.

scholarly journals Nicotine aggravates vascular adiponectin resistance via ubiquitin-mediated adiponectin receptor degradation in diabetic Apolipoprotein E knockout mouse

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Jia Gao ◽  
Jianghong Fan ◽  
Zhijun Meng ◽  
Rui Wang ◽  
Caihong Liu ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Vascular Dysfunction ◽  
Umbilical Vein ◽  
Vascular Ring ◽  
Cytokine Signaling ◽  
High Lipid ◽  
Socs3 Expression ◽  
Umbilical Vein Endothelial Cells ◽  
First Time

AbstractThere is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE−/−) mice was elevated in advance of 2 weeks of diabetic ApoE−/− mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.

scholarly journals Soluble (Pro)Renin Receptor Induces Endothelial Dysfunction and Hypertension in Mice with Diet-Induced Obesity via Activation of AngiotensinII Type 1 Receptor

2021 ◽  
Author(s):  
Ziwei Fu ◽  
Fei Wang ◽  
Xiyang Liu ◽  
Jiajia Hu ◽  
Jiahui Su ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
Elevated Blood Pressure ◽  
H2o2 Production ◽  
No Production ◽  
Ang Ii ◽  
Elevated Blood ◽  
Diet Induced Obesity

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II) dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro; and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

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