scholarly journals The Role of Nrf2 in the PM-Induced Vascular Injury Under Real Ambient Particulate Matter Exposure in C57/B6 Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengyu Gao ◽  
Yuanyuan Ma ◽  
Jing Luo ◽  
Daochuan Li ◽  
Menghui Jiang ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Vascular Injury ◽  
Gene Knockout ◽  
Type I ◽  
Exposure Group ◽  
Ang Ii ◽  
Exposure System ◽  
Nrf2 Signaling Pathway ◽  
Nrf2 Knockout

Short-and long-term exposure to particulate matter (PM) has been associated with cardiovascular disease (CVD). It is well recognized that oxidative stress is a potential major mechanism in PM-induced vascular injuries, in which the nuclear factor E2-related factor 2 (Nrf2) signaling pathway plays a critical role. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential vascular injury and the potential role of Nrf2 in the angiotensin II (Ang II)-associated vascular injury. After 6-or 11-week exposure to PM, the histopathology assay revealed that PM exposure resulted in the thickening of the walls of vascular. After 6 weeks exposure to PM, the ELISA assay revealed that PM exposure resulted in the elevated plasma concentration of Ang II. The expression levels of genes of interest were then further investigated with quantitative real-time PCR. Notably, the results showed that Angiotensinogen (AGT), Angiotensin converting enzyme (ACE) and Angiotensin type I receptor (AT1R) were involved in PM-induced pathological changes. Western blotting for ACE showed similar results. Moreover, the extent of vascular thickening and the Ang II elevation was most prominent in the Nrf2 gene knockout PM exposure group (KOE). Furthermore, the expression of Nrf2 downstream relevant genes (HO1, Nqo1, Gclc, Gsta4) were significantly enhanced in the wildtype PM exposure group (WTE), while those were remarkably suppressed in the Nrf2 gene knockout groups. The ELISA result of monocyte chemoattractant protein-1 (MCP-1) serum levels in the KOE group was significantly higher in relation to that in the Nrf2 knockout control group (KOC). In summary, PM exposure is associated with thickening of vascular wall, while Nrf2 knockout may further enhance this effect. A potential mechanistic contributor of such effects is the activation of ACE/ANGII/AT1R axis, in which Nrf2 played a regulatory role.

Abstract 107: Mir-431 as a Potential Master Regulator in Angiotensin Ii-induced Vascular Injury

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kugeng Huo ◽  
Tlili Barhoumi ◽  
Julio C Fraulob-Aquino ◽  
Chantal Richer ◽  
Mathieu Lajoie ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Molecular Networks ◽  
Type I ◽  
Mirna Cluster ◽  
Mrna Levels ◽  
Ang Ii ◽  
Master Regulator ◽  
Developmental Processes ◽  
Altered Expression ◽  
Total Rna

Objective: Vascular injury is an early manifestation and a cause of end-organ damage in hypertension. microRNAs (miRNAs) play an important role in cardiovascular disease, but their implication in vascular injury is remains unclear. We aim to use RNA sequencing (seq) and a systems biology approach to identify master regulators that mediate global gene expression changes in the course of vascular injury. Methods and Results: Ten week-old male C57BL/6 mice were infused or not with angiotensin (Ang) II (1 μg/kg/min, SC) for 14 days. Blood pressure (BP) was measured by telemetry. Total RNA was extracted from the mesenteric vasculature for total RNA and small RNA-seq. Differentially expressed (DE) miRNAs (23 up and 12 down) and mRNAs (550 up and 256 down) were identified (1.5-fold, q <0.05). Molecular networks were constructed to integrate predicted interactions between DE miRNAs and inversely expressed DE mRNAs and between DE transcription factors (TF) and DE genes. Gene enrichment analysis revealed DE mRNAs involved in extracellular matrix (ECM) and developmental processes regulated by DE miRNAs ( q <1.5E-11). Seventeen upregulated miRNAs are located in the miRNA cluster of the Dlk1-Dio3 region that is highly conserved in humans, 9 of which had expression levels correlated with BP ( P <0.05). Among those 9, miR-431 that ranked first as DE miRNA ( q <0.0005) and is 100% conserved in humans, and a conserved putative DE target, a BP-correlated ( P <0.05) TF ETS homologous factor ( Ehf ), which regulates numerous ECM genes including collagen type I α1 ( Col1a1 ), were selected for functional studies. Transfection of a miR-431 mimic in human aortic smooth muscle cells (HASMCs) decreased Ehf (0.1±0.1-fold, P <0.001) and increased Ehf -suppressing target Col1a1 (1.7±0.5-fold, P <0.001) mRNA levels. Transfection of a miR-431 inhibitor caused reciprocal effects ( P <0.05). Ehf siRNA knockdown increased Col1a1 (1.2±0.1-fold, P <0.001) mRNA levels. Conclusions: Ang II infusion altered expression of miRNAs in the Dlk1-Dio3 cluster and genes involved in ECM and developmental processes. miR-431 targets TF Ehf , which leads to increased Col1a1 in HASMCs. miR-431 may act as a master regulator for vascular injury and could be a potential therapeutic target.

The Role of Apoptosis in Myocyte Death During Cardiac Hypertrophy

2001 ◽  
Vol 7 (S2) ◽  
pp. 596-597
Author(s):  
E.C. Goldsmith ◽  
J.G. Davis ◽  
X. Yan ◽  
B.H. ᒫorell ◽  
T.K. Borg ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Development ◽  
Mechanical Stimulus ◽  
Type I ◽  
Integrin Subunit ◽  
Ang Ii ◽  
Adult Rat ◽  
Rat Myocytes

Apoptotic events can be the result of both cell anchorage-dependent and independent mechanisms. The term “anoikis” has been used to describe apoptotic events resulting from a lack of cell-ECM contact (Frisch and Francis, 1994). The integrin heterodimer α5β1 has been implicated in several systems as providing protection against apoptosis. Previous studies have demonstrated that the α5 integrin subunit is present only during cardiac development and conditions of cardiac hypertrophy and is not found in normal adult rat myocytes (Terracio et al., 1991). Cell anchorage-independent apoptosis can result from a variety of factors including biochemical and mechanical stimulus. Angiotensin II (Ang II) has been implicated as a modulator of myocyte apoptosis acting through the angiotensin II type I receptor (Kajstura et al., 1997). The role of a second Ang II receptor, angiotensin II type 2 receptor, has not been determined. The role of apoptosis in myocyte cell death during heart failure remains unclear.

Abstract 083: γ/δ T Cells Play a Role in Development of Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Muhammad O Mian ◽  
Julio C Fraulob-Aquino ◽  
Ku-Geng Huo ◽  
Tlili Barhoumi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Vascular Injury ◽  
Inflammatory Markers ◽  
Supervised Machine Learning ◽  
T Cell Subsets ◽  
Ang Ii ◽  
Adaptive Immune

Objective: Both innate antigen-presenting cells and the adaptive immune system have been shown to play a role in the development of hypertension. Nevertheless, the T cell subsets involved in the pathophysiology of hypertension remains unclear. There is a small subset of “innate-like” T cells expressing the γ/δ T cell receptor (TCR) rather than the α/β TCR that could play a role bridging the innate and adaptive immune systems. We previously observed that angiotensin (Ang) II caused an increase in number and activation of γ/δ T cells and Ang II-induced systolic blood pressure (SBP) rise and vascular injury were blunted in Tcr δ -/- mice, which are devoid of γ/δ T cells. In order to further characterize the role of γ/δ T cells in hypertension, we determined whether Ang II-effects would be blunted by antibody-induced depletion of γ/δ T cells. In addition, we tested whether SBP in human could be predicted by combining the expression of genes encoding TCRGC (TCR gamma constant region) and pro-inflammatory markers of γ/δ T cells in peripheral blood mononuclear cells (PBMC). Method and Results: Thirteen to 15-week old male C57BL/6 wild-type (WT) mice were infused with Ang II (490 ng/kg/min, SC) for 14 days and injected IP with anti-γ/δ TCR or control isotype antibodies 1 day before and at day 6 of Ang II infusion. Depletion of γ/δ T cells decreased SBP (147±2 vs 167 ± 3 mm Hg, P <0.05) and restored mesenteric artery relaxation responses to acetylcholine (E max : 90±4 vs 62 ± 8%, P <0.05) compared to isotype antibody-treated mice. Using the SBP data and the PBMC gene expression profile (GSE12288) of 222 human subjects, we predicted with a supervised machine learning approach SBP by combining the gene expression of TCRGC and pro-inflammatory makers including interleukin-17A, interferon-γ and their receptors (R=0.23, P <0.001). Conclusion: Antibody-induced depletion further demonstrates the role of γ/δ T cells in Ang II-induced SBP elevation and vascular injury. Prediction of SBP using PBMC gene expression of γ/δ T cells and pro-inflammatory markers suggests that γ/δ T cells contribute to the development of human hypertension.

Abstract P162: In vivo miR-431 Inhibition Protects Against Vascular Damage and Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ku-Geng Huo ◽  
Julio C. Fraulob-Aquino ◽  
Tlili Barhoumi ◽  
Chantal Richer ◽  
Suellen C. Coelho ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Type I Collagen ◽  
Vascular Damage ◽  
Mesenteric Arteries ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Type I ◽  
Ang Ii

Background: Vascular injury is an early manifestation of hypertension. microRNAs (miRNAs) play an important role in cardiovascular disease, but their implication in vascular injury remains unclear. Using small and total RNA sequencing, we identified in murine mesenteric arteries (MAs) a conserved angiotensin (Ang) II-upregulated Dlk1-Dio3 miRNA miR-431 that correlated with blood pressure (BP), and an Ang II-downregulated BP-correlated conserved putative miR-431 target, the transcriptional factor ETS homologous factor ( Ehf ). miR-431 might be involved in vascular remodeling as Ehf regulates expression of extracellular matrix genes including alpha-1 type I collagen ( Col1a1 ) and of other Dlk1-Dio3 miRNAs. In this study, we proposed to validate the miR-431- Ehf - Col1a1 interaction in vitro and in vivo , and determine whether miR-431 inhibition antagonizes angiotensin (Ang) II-induced hypertension and vascular injury. Methods and Results: Transfection of miR-431 mimics into human aortic smooth muscle cells decreased Ehf expression (0.13±0.05 fold, P <0.001) and increased Col1a1 (1.7±0.5 fold, P <0.01), whereas miR-431 inhibitors increased Ehf (1.5±0.2 fold, P <0.001) and decreased Col1a1 (0.89±0.11 fold, P <0.05). Ehf siRNA transfection increased 1.2±0.1 fold Col1a1 ( P <0.01). Co-transfection of miR-431 mimics with luciferase reporter vectors that contain the wild-type but not mutated miR-431 human EHF 3’ UTR binding site decreased 0.51±0.01 fold ( P <0.05) luciferase expression compared to scrambled mimics. miR-431 inhibitor IV injection in mice at day 0 and 7 of Ang II infusion decreased miR-431 (0.16±0.05 fold, P <0.01), Col1a1 (0.58±0.11 fold, P <0.05), increased Ehf (2.9±0.8 fold, P <0.05) in MAs, delayed BP elevation ( P <0.01), improved endothelium-dependent relaxation (33±8 vs 64±7%, P <0.05) and reduced vascular stiffness (strain at 140mmHg: 0.68±0.02 vs 0.58±0.02 ΔD/D, P <0.01) compared to scrambled mimics-injected Ang II-infused mice. Conclusion and Perspectives: miR-431 and its target Ehf may act as master regulators in the pathophysiology of vascular damage in hypertension. miR-431 inhibition has the potential to serve as a novel therapeutic approach for treatment of vascular damage and hypertension.

scholarly journals Role of type I and type II interferon responses in recovery from infection with an encephalitic flavivirus

2003 ◽  
Vol 84 (3) ◽  
pp. 567-572 ◽  
Author(s):  
Mario Lobigs ◽  
Arno Müllbacher ◽  
Yang Wang ◽  
Megan Pavy ◽  
Eva Lee
Keyword(s):  
Nitric Oxide ◽  
Gene Knockout ◽  
Intravenous Route ◽  
Type I ◽  
Virus Growth ◽  
Susceptibility To Infection ◽  
Ifn Γ ◽  
Knockout Animals ◽  
Interferon Responses

We have investigated the contribution of the interferon (IFN)-α/β system, IFN-γ and nitric oxide to recovery from infection with Murray Valley encephalitis virus, using a mouse model for flaviviral encephalitis where a small dose of virus was administered to 6-week-old wild-type and gene knockout animals by the intravenous route. We show that a defect in the IFN-α/β responses results in uncontrolled extraneural virus growth, rapid virus entry into the brain and 100 % mortality. In contrast, mice deficient in IFN-γ or nitric oxide production display an only marginally increased susceptibility to infection with the neurotropic virus.

scholarly journals Angiotensin-(1-7) and Its Effects in the Kidney

2009 ◽  
Vol 9 ◽  
pp. 522-535 ◽  
Author(s):  
Marc Dilauro ◽  
Kevin D. Burns
Keyword(s):  
Blood Pressure ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Gene Knockout ◽  
Collecting Duct ◽  
Tyrosine Phosphatase ◽  
The Body ◽  
Ang Ii

Angiotensin-(1-7) (Ang-[1-7]) is a heptapeptide member of the renin-angiotensin system (RAS), and acts as a vasodilator and antagonist of angiotensin II (Ang II) in the vasculature. The role of Ang-(1-7) in regulating kidney function is not well understood. Within the kidneys, Ang-(1-7) is generated by angiotensin-converting enzyme 2 (ACE2)–mediated degradation of Ang II, sequential cleavage of the precursor angiotensin I (Ang I) by ACE2 and ACE, or the actions of brush-border membrane peptidases on Ang I. Ang-(1-7) mediates its effects via binding to kidney Mas receptors, although some actions may occur via Ang II AT1or AT2receptors.In vitrostudies suggest that Ang-(1-7) is an intrarenal vasodilator. Ang-(1-7) has been reported to induce either natriuresis/diuresis or sodium and water retention, via modulation of sodium transporters in the proximal tubule and loop of Henle, and collecting duct water transport. In the proximal tubule, Ang-(1-7) antagonizes growth-promoting signaling pathways via activation of a protein tyrosine phosphatase, whereas in mesangial cells, Ang-(1-7) stimulates cell growth via activation of mitogen-activated protein kinases. The phenotype of the Mas gene knockout mouse suggests that Ang-(1-7)–signaling events exert cardiovascular protection by regulating blood pressure, and by limiting production of reactive oxygen species and extracellular matrix proteins. Ang-(1-7) also protects against renal injury in the renal wrap hypertension model, independent of effects on blood pressure. In diabetic nephropathy, however, the role of Ang-(1-7) on disease progression remains unclear. In summary, Ang-(1-7) and its receptor Mas have emerged as important components of the intrarenal RAS. The signaling and downstream effects of Ang-(1-7) in the kidney are complex and appear to be cell specific. The body of evidence suggests that Ang-(1-7) is protective against endothelial dysfunction or Ang II–stimulated proximal tubular injury, although the overall effects on glomerular function require further study.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

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