Abstract 629: Differential Expression Of Angiotensin-(1-12)/chymase In Human Atrial Tissue

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sayaka Nagata ◽  
Jasmina Varagic ◽  
Stephen W Simington ◽  
Sarfraza Ahmad ◽  
Jessica L VonCannon ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Heart Surgery ◽  
Critical Role ◽  
Disease Process ◽  
The Novel ◽  
Ang Ii ◽  
Atrial Tissue ◽  
Right Atria ◽  
Tissues Expression

Proangiotensin-12 [Ang-(1-12)] is a C-terminal extended form of Ang I [Ang I-Leu-Tyr] originally isolated from the rat small intestine. Additional studies showed that while both ACE and chymase cleaved Ang II from Ang-(1-12) in the rat heart, chymase but not ACE metabolized Ang-(1-12) in the human heart. This study characterized the expression of Ang-(1-12)/chymase in human atrial tissue to gain an insight into the potential role of this Ang II-forming substrate in cardiac disease. Left (LA; n=16) and right (RA; n=14) portions of atrial appendages were obtained from humans undergoing heart surgery. Quantitative Ang-(1-12) immunohistochemistry (Image J software) was performed using a high affinity purified antibody directed to the COOH-terminus of the full length of human Ang-(1-12) in all samples (LA: male=13 and female=3; RA: male=9 and female=5). Chymase activity was determined by HPLC in plasma membranes from left (males=7 and females=3) and right atria (males=7 and females=3). Quantitative analysis of Ang-(1-12) expression revealed significantly higher Ang-(1-12) expression in LA (Intensity: 35.37±6.24 units) versus RA (19.38±2.38 units, p=0.03) appendages. Likewise, chymase activity was higher in the LA (52.02±5.20 fmol/mg/min) compared to RA (18.09±3.05, p<0.0001) tissues. Expression of Ang-(1-12) in atria did not correlate with subject’s age, disease process or medications. The novel demonstration of higher Ang-(1-12) expression and chymase activity in human LA reveals a critical role of this tissue Ang II forming axis in modulating the diastolic and systolic properties of this cardiac cavity.

scholarly journals Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+ signaling in vascular endothelial cells

2018 ◽  
Vol 315 (5) ◽  
pp. H1477-H1485 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Hiromi Imamura ◽  
Joji Ando
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Atp Release ◽  
Vascular Endothelial ◽  
The Novel ◽  
Caveolin 1 ◽  
Atp Generation

Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nhat-Tu Le ◽  
Yuichiro Takei ◽  
Chang-Hoon Woo ◽  
Tetsuro Shishido ◽  
Yan Lu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Active Form ◽  
E3 Ligase ◽  
Left Ventricular ◽  
Ang Ii ◽  
Lv Dysfunction ◽  
On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

Introduction: Religion and the Novel

2019 ◽  
pp. 3-33
Author(s):  
Christina Phillips
Keyword(s):  
Postcolonial Studies ◽  
Critical Role ◽  
Postcolonial Literature ◽  
The Other ◽  
The Novel ◽  
Religion And Literature ◽  
Religious Other ◽  
Role Of Religion ◽  
The Relationship

This chapter introduces the topic of religion and literature, theorises the novel as a secular genre, and develops a concept of religion as the other in the Arabic novel. It begins with a discussion of the relationship between religion and literature, identifying imagination, metaphorical language and mythos as areas of overlap, before turning to the question of religion and the Arabic novel as a modern form which eschews faith and dogma but is nevertheless packed with religious themes, images, characters, language and intertextuality. This is accounted for by the form’s secularism, which is theorised in terms of Charles Taylor’s conditions of belief. Literary secularism is not static and stable however, thus religion emerges as the other in the Egyptian novel, with all the ambivalence which alterity characteristically entails. This religious other calls into question postcolonial studies’ over-valorisation of the East/West binary insofar as it has obscured the critical role of religion in Arab postcolonial literature and identity.

scholarly journals The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhaoji Pan ◽  
Yiqing Tian ◽  
Guoping Niu ◽  
Chengsong Cao
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Wound Repair ◽  
Critical Role ◽  
The Novel ◽  
Potential Biomarker ◽  
Underlying Mechanisms ◽  
Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

ANG II-induced excitation of paraventricular nucleus magnocellular neurons: a role for glutamate interneurons

2004 ◽  
Vol 286 (5) ◽  
pp. R894-R902 ◽  
Author(s):  
K. J. Latchford ◽  
A. V. Ferguson
Keyword(s):  
Paraventricular Nucleus ◽  
Kynurenic Acid ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Ang Ii ◽  
Magnocellular Neurons ◽  
Whole Cell Patch Clamp ◽  
Electrolyte Homeostasis ◽  
Hypothalamic Slices

The hypothalamic paraventricular nucleus (PVN) plays a critical role in cardiovascular and neuroendocrine regulation. ANG II (ANG) acts throughout the periphery in the maintenance of fluid-electrolyte homeostasis and has also been demonstrated to act as a neurotransmitter in PVN exerting considerable influence on neuronal excitability in this nucleus. The mechanisms underlying the ANG-mediated excitation of PVN magnocellular neurons have yet to be determined. We have used whole cell patch-clamp techniques in hypothalamic slices to examine the effects of ANG on magnocellular neurons. Application of ANG resulted in a depolarization of magnocellular neurons, a response that was abolished in TTX, suggesting an indirect mechanism of action. Interestingly, ANG also increased the frequency of excitatory postsynaptic potentials/currents in magnocellular neurons, an effect that was abolished after application of the glutamate antagonist kynurenic acid. ANG was without effect on the amplitude of excitatory postsynaptic currents, suggesting a presynaptic action on an excitatory interneuron within PVN. The ANG-induced depolarization was shown to be sensitive to kynurenic acid, revealing the requisite role of glutamate in mediating the ANG-induced excitation of magnocellular neurons. These observations indicate that the ANGergic excitation of magnocellular PVN neurons are dependent on an increase in glutamatergic input and thus highlight the importance of a glutamate interneuron in mediating the effects of this neurotransmitter.

scholarly journals Role of the renin-angiotensin system in the development of severe COVID-19 in hypertensive patients

2020 ◽  
Vol 319 (4) ◽  
pp. L596-L602
Author(s):  
Rodrigo Pacheco Silva-Aguiar ◽  
Diogo Barros Peruchetti ◽  
Patricia Rieken Macedo Rocco ◽  
Alvin H. Schmaier ◽  
Patrícia Machado Rodrigues e Silva ◽  
...  
Keyword(s):  
Critical Role ◽  
Renin Angiotensin System ◽  
Multiple Organ ◽  
Ang Ii ◽  
Angiotensin System ◽  
Hypertensive Patients ◽  
Renin Angiotensin ◽  
Therapeutic Benefits ◽  
Global Threat

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.

Role of EGFR/ErbB2 and PI3K/AKT/e-NOS in Lycium barbarum polysaccharides Ameliorating Endothelial Dysfunction Induced by Oxidative Stress

2019 ◽  
Vol 47 (07) ◽  
pp. 1523-1539 ◽  
Author(s):  
Wenjuan Zhang ◽  
Huifang Yang ◽  
Lingqin Zhu ◽  
Yan Luo ◽  
Lihong Nie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Critical Role ◽  
Ang Ii ◽  
Lycium Barbarum ◽  
Underlying Mechanisms ◽  
Lycium Barbarum Polysaccharides

Lycium barbarum polysaccharides (LBP) are the major ingredients of wolfberry. In this study, we investigated the role of LBP in endothelial dysfunction induced by oxidative stress and the underlying mechanisms using thoracic aortic endothelial cells of rat (RAECs) as a model. We found that Ang II inhibits cell viability of RAECs with 10[Formula: see text][Formula: see text]mol/L of Ang II treatment for 24[Formula: see text]h most potential ([Formula: see text]), the level of reactive oxygen species (ROS) is increased by Ang II treatment ([Formula: see text]), and the expression of Occludin and Zonula occludens-1 (ZO-1) is decreased by Ang II treatment ([Formula: see text]). However, preincubation of cells with LBP could inhibit the changes caused by Ang II, LBP increased cell viability ([Formula: see text]), decreased the level of ROS ([Formula: see text]), and up-regulated the expression of Occludin ([Formula: see text]) and ZO-1. In addition, Ang II treatment increased the expression of EGFR and p-EGFR (Try1172) and which can be inhibited by LBP. On the contrary, expression of ErbB2, p-ErbB2 (Try1248), PI3K, p-e-NOS (Ser1177) ([Formula: see text]), and p-AKT (Ser473) ([Formula: see text]) was inhibited by Ang II treatment and which can be increased by LBP. Treatment of the cells with inhibitors showed that the regulation of p-e-NOS and p-AKT expression by Ang II and LBP can be blocked by PI3K inhibitor wortmannin but not EGFR and ErbB2 inhibitor AC480. Taken together, our results suggested that LBP plays a critical role in maintaining the integrality of blood vessel endothelium through reduced production of ROS via regulating the activity of EGFR, ErbB2, PI3K/AKT/e-NOS, and which may offer a novel therapeutic option in the management of endothelial dysfunction.

scholarly journals Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs

2019 ◽  
Vol 116 (26) ◽  
pp. 13006-13015 ◽  
Author(s):  
Wang Wang ◽  
Mengcheng Shen ◽  
Conrad Fischer ◽  
Ratnadeep Basu ◽  
Saugata Hazra ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Critical Role ◽  
Neutral Endopeptidase ◽  
Negative Regulator ◽  
Ang Ii ◽  
Direct Role ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

scholarly journals The YAP1 Homolog–Mediated Oxidative Stress Tolerance Is Crucial for Pathogenicity of the Necrotrophic Fungus Alternaria alternata in Citrus

2009 ◽  
Vol 22 (8) ◽  
pp. 942-952 ◽  
Author(s):  
Ching-Hsuan Lin ◽  
Siwy Ling Yang ◽  
Kuang-Ren Chung
Keyword(s):  
Oxidative Stress ◽  
Alternaria Alternata ◽  
Critical Role ◽  
Disease Process ◽  
Brown Spot ◽  
Null Mutant ◽  
Wild Type ◽  
Protein Fusion ◽  
Fungal Pathogenicity

Citrus brown spot disease is caused by the necrotrophic fungus Alternaria alternata. Its pathogenic capability has been thought to depend exclusively on the production of host-selective ACT toxin. However, circumvention of plant defenses is also likely to be important for the disease process. To investigate the fungal response to host-generated reactive oxygen species (ROS), we cloned and characterized the AaAP1 gene of A. alternata, which encodes a polypeptide resembling yeast YAP1-like transcriptional activators implicated in cellular responses to stress. Expression of the AaAP1 gene in a wild-type strain was primarily induced by H2O2 or ROS-generating oxidants. Using a loss-of-function mutation in the AaAP1 gene, we demonstrated an essential requirement for oxidative tolerance during the host invasion step. Mutants lacking AaAP1 showed increased sensitivity to H2O2 and loss of fungal pathogenicity. The ΔAaAP1 null mutant did not cause any visible necrotic lesions on wounded or unwounded leaves of citrus cv. Minneola. Compared with the wild type, the null mutant displayed lower catalase, peroxidase, and superoxide dismutase activities. All mutant phenotypes were restored to the wild type in fungal strains expressing a functional copy of AaAP1. Upon exposure to H2O2, the AaAP1::sGFP (synthetic green fluorescent protein) fusion protein became localized in the nucleus. Inoculation of the mutant with NADPH oxidase inhibitors partially restored fungal pathogenicity. Our results highlight the global regulatory role of a YAP1 homolog in response to oxidative stress in A. alternata and provide insights into the critical role of ROS detoxification in the pathogenicity of A. alternata.

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