scholarly journals Role of microRNA 690 in Mediating Angiotensin II Effects on Inflammation and Endoplasmic Reticulum Stress

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1327
Author(s):  
Kalhara R. Menikdiwela ◽  
Latha Ramalingam ◽  
Mostafa M. Abbas ◽  
Halima Bensmail ◽  
Shane Scoggin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Ang Ii ◽  
Protective Function

Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

scholarly journals SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)–Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function

2020 ◽  
Author(s):  
Tong Wei ◽  
Jing Gao ◽  
Chenglin Huang ◽  
Bei Song ◽  
Mengwei Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Metabolic Phenotype ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Sirtuin 3 ◽  
Metabolic Switch ◽  
Brown Adipocytes ◽  
Perivascular Adipose Tissue

Objective: Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1β secretion in myeloid SIRT3 knockout (SIRT3 − / − ) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow–derived macrophages induces IL-1β production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1β secretion. Furthermore, the blockade of IL-1β from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3 −/− ) mice exhibited reduced IL-1β production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. Conclusions: SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.

Melatonin plays a pivotal role in conferring tolerance against endoplasmic reticulum stress via mitogen-activated protein kinases and bZIP60 in Arabidopsis thaliana

2018 ◽  
Vol 1 (1) ◽  
pp. 94-108 ◽  
Author(s):  
Hyoung Yool Lee ◽  
Kyoungwhan Back
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secretory Protein ◽  
Protective Role ◽  
Mitogen Activated Protein Kinase ◽  
Ion Leakage ◽  
Defense Systems ◽  
Mitogen Activated Protein ◽  
Stress Damage

Melatonin has diverse roles as a signaling molecule that activates a number of downstream defense systems against various biotic and abiotic stresses in plants. However, there have been no reports regarding a direct protective role of melatonin against endoplasmic reticulum (ER) stress. Here, we report that exogenous melatonin treatment attenuated ER stress damage by preserving ER structure and enhancing secretory protein folding capacity in response to tunicamycin treatment. Further transgenic experiments indicated that melatonin-deficient snat1 mutant was hypersensitive to ER stress, whereas melatonin-proficient SNAT1 overexpression (OE) was tolerant to ER stress, as evidenced by reduced ion leakage and higher transcript levels of ER chaperones, including luminal binding protein (BIP) 2, BIP3, and CNX1, compared to wild-type controls. Moreover, this melatonin-mediated ER stress tolerance was dependent on the bZIP60 transcription factor and mitogen-activated protein kinase. Our data suggest that melatonin is actively involved in maintaining homeostasis of the ER during normal plant growth, and also has a protective effect against many environmental stressors that induce ER stress.

scholarly journals Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

2016 ◽  
Vol 310 (9) ◽  
pp. C755-C763 ◽  
Author(s):  
Mingfang Jiang ◽  
Qiang Yun ◽  
Feng Shi ◽  
Guangming Niu ◽  
Yang Gao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Binding Protein ◽  
Quantitative Polymerase Chain Reaction ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Stress Signaling

Endoplasmic reticulum (ER) stress has been linked to the pathogenesis of Parkinson's disease (PD). However, the role of microRNAs (miRNAs) in this process involved in PD remains poorly understood. Recent studies indicate that miR-384-5p plays an important role for cell survival in response to different insults, but the role of miR-384-5p in PD-associated neurotoxicity remains unknown. In this study, we investigated the role of miR-384-5p in an in vitro model of PD using dopaminergic SH-SY5Y cells treated with rotenone. We found that miR-384-5p was persistently induced by rotenone in neurons. Also, the inhibition of miR-384-5p significantly suppressed rotenone-induced neurotoxicity, while overexpression of miR-384-5p aggravated rotenone-induced neurotoxicity. Through bioinformatics and dual-luciferase reporter assay, miR-384-5p was found to directly target the 3′-untranslated region of glucose-regulated protein 78 (GRP78), the master regulator of ER stress sensors. Quantitative polymerase chain reaction and Western blotting analysis showed that miR-384-5p negatively regulated the expression of GRP78. Inhibition of miR-384-5p remarkably suppressed rotenone-evoked ER stress, which was evident by a reduction in the phosphorylation of activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α). The downstream target genes of ER stress including CCAAT/enhancer-binding protein-homologous protein (CHOP) and X box-binding protein-1 (XBP-1) were also decreased by the miR-384-5p inhibitor. In contrast, overexpression of miR-384-5p enhanced ER stress signaling. In addition, knockdown of GRP78 significantly abrogated the inhibitory effect of miR-384-5p inhibitors on cell apoptosis and ER stress signaling. Moreover, we observed a significant increase of miR-384-5p expression in primary neurons induced by rotenone. Taken together, our results suggest that miR-384-5p mediated ER stress by negatively regulating GRP78 and that miR-384-5p inhibition might be a novel and promising approach for the treatment of PD.

scholarly journals I-κB Kinase-ε Deficiency Attenuates the Development of Angiotensin II-Induced Myocardial Hypertrophy in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yide Cao ◽  
Liangpeng Li ◽  
Yafeng Liu ◽  
Ganyi Chen ◽  
Zhonghao Tao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Myocardial Hypertrophy ◽  
Peptide Hormone ◽  
Mitogen Activated Protein Kinase ◽  
Mouse Heart ◽  
Ang Ii ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

I-κB kinase-ε (IKKε) is a member of the IKK complex and a proinflammatory regulator that is active in many diseases. Angiotensin II (Ang II) is a vasoconstricting peptide hormone, and Ang II-induced myocardial hypertrophy is a common cardiovascular disease that can result in heart failure. In this study, we sought to determine the role of IKKε in the development of Ang II-induced myocardial hypertrophy in mice. Wild-type (WT) and IKKε-knockout (IKKε-KO) mice were generated and infused with saline or Ang II for 8 weeks. We found that WT mouse hearts have increased IKKε expression after 8 weeks of Ang II infusion. Our results further indicated that IKKε-KO mice have attenuated myocardial hypertrophy and alleviated heart failure compared with WT mice. Additionally, Ang II-induced expression of proinflammatory and collagen factors was much lower in the IKKε-KO mice than in the WT mice. Apoptosis and pyroptosis were also ameliorated in IKKε-KO mice. Mechanistically, IKKε bound to extracellular signal-regulated kinase (ERK) and the mitogen-activated protein kinase p38, resulting in MAPK/ERK kinase (MEK) phosphorylation, and IKKε deficiency inhibited the phosphorylation of MEK-ERK1/2 and p38 in mouse heart tissues after 8 weeks of Ang II infusion. The findings of our study reveal that IKKε plays an important role in the development of Ang II-induced myocardial hypertrophy and may represent a potential therapeutic target for the management of myocardial hypertrophy.

Abstract 1221: Targeted Deletion of ROCK2 in Cardiomyocytes Prevents Angiotensin II-Induced Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ryuji Okamoto ◽  
Kensuke Noma ◽  
Naoki Sawada ◽  
Yukio Hiroi ◽  
Ping-Yen Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Heart Weight ◽  
Ang Ii ◽  
Targeted Deletion

Background - Previous studies have shown that Rho kinase (ROCK) inhibitors prevent the development of cardiac hypertrophy. Because ROCK inhibitors inhibit both ROCK isoforms, ROCK1 and ROCK2, the isoform-specific role of ROCK cannot be elucidated from these studies. Hence, a genetic approach with targeted deletion of ROCK in cardiomyocytes provides the best opportunity towards understanding the role of ROCK isoforms in the development of cardiac hypertrophy. Previous studies showed that ROCK1 KO mice develop cardiac hypertrophy to angiotensin II infusion similar to WT mice, but do not develop cardiac fibrosis. However, the role of ROCK2 in the development of cardiac hypertrophy remains to be determined. Methods and Results - Mice deficient in cardiomyocyte-specific ROCK2 (c-ROCK2 −/− ) were generated by crossing mice with loxP-flanked ROCK2 allele with transgenic mice expressing a Cre protein under the control of the cardiomyocyte-specific alpha-myosin heavy chain promoter. The ROCK2 expression levels in the c-ROCK2 −/− mice heart was decreased to less than 30% compared with wild-type mice (ROCK2 +/+ mice) in the whole heart. Heart rate, blood pressures and cardiac systolic function were normal in c-ROCK2 −/− mice. Ang II (400ng/kg/min) or vehicle was subcutaneously infused into c-ROCK2 −/− and ROCK2 +/+ male mice (each group; n=10) for 28 days. Ang II-induced cardiac hypertrophy assessed by an increase in heart weight, left ventricular mass, myocyte cross-sectional area and cardiac hypertrophy-related genes expressions were attenuated in c-ROCK2 −/− mice compared with ROCK2 +/+ mice. The basal activity of extracellular signal-regulated kinase (ERK) were similar in hearts between two groups but the activation of ERK was attenuated and the activity was downregulated earlier in c-ROCK2 −/− than in ROCK2 +/+ mice. The activity of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and Akt activity were similar between two groups. Conclusions - These results indicate that ROCK2 is necessary for Ang II-induced cardiac hypertrophy. The mechanism, in part, involves the activation of ERK by ROCK2. Thus, selective ROCK2 inhibitors may be beneficial for preventing cardiac hypertrophy.

scholarly journals Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruna Bezerra Lins ◽  
Fernando Augusto Malavazzi Casare ◽  
Flávia Ferreira Fontenele ◽  
Guilherme Lopes Gonçalves ◽  
Maria Oliveira-Souza
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Angiotensin Ii ◽  
Protein Expression ◽  
Er Stress ◽  
Mrna Expression ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Ang Ii ◽  
Gene And Protein Expression

High plasma angiotensin II (Ang II) levels are related to many diseases, including hypertension, and chronic kidney diseases (CKDs). Here, we investigated the relationship among prolonged Ang II infusion/AT1 receptor (AT1R) activation, oxidative stress, and endoplasmic reticulum (ER) stress in kidney tissue. In addition, we explored the chronic effects of Ang II on tubular Na+ transport mechanisms. Male Wistar rats were subjected to sham surgery as a control or prolonged Ang II treatment (200 ng⋅kg–1⋅min–1, 42 days) with or without losartan (10 mg⋅kg–1⋅day–1) for 14 days. Ang II/AT1R induced hypertension with a systolic blood pressure of 173.0 ± 20 mmHg (mmHg, n = 9) compared with 108.0 ± 7 mmHg (mmHg, n = 7) in sham animals. Under these conditions, gene and protein expression levels were evaluated. Prolonged Ang II administration/AT1R activation induced oxidative stress and ER stress with increased Nox2, Nox4, Cyba and Ncf1 mRNA expression, phosphorylated PERK and eIF2α protein expression as well as Atf4 mRNA expression. Ang II/AT1R also raised Il1b, Nfkb1 and Acta2 mRNA expression, suggesting proinflammatory, and profibrotic effects. Regarding Na+ tubular handling, Ang II/AT1R enhanced cortical non-phosphorylated and phospho/S552/NHE3, NHE1, ENaC β, NKCC2, and NCC protein expression. Our results also highlight the therapeutic potential of losartan, which goes beyond the antihypertensive effect, playing an important role in kidney tissue. This treatment reduced oxidative stress and ER stress signals and recovered relevant parameters of the maintenance of renal function, preventing the progression of Ang II-induced CKD.

scholarly journals Mineralocorticoid Receptor in Myeloid Cells Mediates Angiotensin II-Induced Vascular Dysfunction in Female Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Camila Manrique-Acevedo ◽  
Jaume Padilla ◽  
Huma Naz ◽  
Makenzie L. Woodford ◽  
Thaysa Ghiarone ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Vascular Dysfunction ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Ang Ii ◽  
Female Mice

Enhanced mineralocorticoid receptor (MR) signaling is critical to the development of endothelial dysfunction and arterial stiffening. However, there is a lack of knowledge about the role of MR-induced adipose tissue inflammation in the genesis of vascular dysfunction in women. In this study, we hypothesize that MR activation in myeloid cells contributes to angiotensin II (Ang II)-induced aortic stiffening and endothelial dysfunction in females via increased pro-inflammatory (M1) macrophage polarization. Female mice lacking MR in myeloid cells (MyMRKO) were infused with Ang II (500 ng/kg/min) for 4 weeks. This was followed by determinations of aortic stiffness and vasomotor responses, as well as measurements of markers of inflammation and macrophage infiltration/polarization in different adipose tissue compartments. MyMRKO mice were protected against Ang II-induced aortic endothelial stiffening, as assessed via atomic force microscopy in aortic explants, and vasorelaxation dysfunction, as measured by aortic wire myography. In alignment, MyMRKO mice were protected against Ang II-induced macrophage infiltration and M1 polarization in visceral adipose tissue (VAT) and thoracic perivascular adipose tissue (tPVAT). Collectively, this study demonstrates a critical role of MR activation in myeloid cells in the pathogenesis of vascular dysfunction in females associated with pro-inflammatory macrophage polarization in VAT and tPVAT. Our data have potential clinical implications for the prevention and management of cardiovascular disease in women, who are disproportionally at higher risk for poor outcomes.

Sign in / Sign up

Export Citation Format

Share Document