Abstract P274: Inhibition Of Abnormal Exosome Release Prevents Excessive Aortic Stiffness And Relaxation Dysfunction In Diet-induced Obesity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Javad Habibi ◽  
Vincent G DeMarco ◽  
Dongqing Chen ◽  
Jack L. Hulse ◽  
Adam Whaley-connell ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Aortic Stiffness ◽  
Blood Pressure Measurement ◽  
Cell Communication ◽  
Cell Types ◽  
Vascular Relaxation ◽  
Diet Induced Obesity ◽  
Diastolic Relaxation ◽  
Aortic Stiffening

Interactions between over-nutrition and abnormal exosome release impact insulin sensitivity and the development of cardiovascular disease (CVD). Recent data have shown that exosomes can be released from various cell types, including adipocytes and vascular cells, and that they exist in body fluids and tissues functioning as mediators of cell-cell communication. However, the specific role of exosomes in diet-induced excessive vascular stiffness and hypertension has not been explored. Accordingly, we hypothesized that abnormal release of exosomes contributes to western diet (WD)- induced aortic stiffening and impaired vascular diastolic relaxation. We further posited that GW4869, an antagonist of neutral sphingomyelinase 2 (nSMase2) which promotes exosome production and release, would prevent WD-induced aortic stiffening and impaired vascular relaxation. Six week-old female C57BL/6L mice were fed a mouse chow (CD) or WD containing excess fat (46%) and fructose (17.5%) for 16 weeks with or without GW4849. To this point, 200 μl of 0.3 mg/mL GW4869 in 0.9% normal saline (60 μg/mouse; 2-2.5 μg/g body weight) was injected intraperitoneally every 48 hours for 12 weeks. 16 weeks of WD induced an increase of aortic stiffness as examined by pulse wave velocity (PWV) and impaired the aortic vasodilation responses to acetylcholine (Ach) and sodium nitroprusside (SNP) (10 -9 -10 -4 mol/L). However, GW4869 treatment prevented the WD-induced excessive aortic stiffness, as well as impairment of endothelium dependent/independent vascular relaxation. There were no significant differences in blood pressure between each group examined by tail cuff blood pressure measurement. These findings support the hypothesis that abnormal release of exosomes play an important role in WD-induced excessive aortic stiffness, impaired vascular relaxation and CVD in diet-induced obesity.

Abstract P231: Inhibition of Mir-762 Prevents and Reverses Ang II Induced Aortic Stiffening

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Aortic Stiffness ◽  
Fold Increase ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

scholarly journals Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

4open ◽  
2019 ◽  
Vol 2 ◽  
pp. 11 ◽  
Author(s):  
Björn L.D.M. Brücher ◽  
Ijaz S. Jamall
Keyword(s):  
Extracellular Matrix ◽  
Chronic Inflammation ◽  
Genetic Material ◽  
Cell Communication ◽  
Cell Types ◽  
Complex Signaling ◽  
Different Cell Types ◽  
Multiple Signaling ◽  
Extracellular Environment

Fibroblasts are actively involved in the creation of the stroma and the extracellular matrix which are important for cell adhesion, cell–cell communication, and tissue metabolism. The role of fibrosis in carcinogenesis can be examined by analogy to tissues of various cancers. The orchestration of letters in the interplay of manifold components with signaling and crosstalk is incompletely understood but available evidence suggests a hitherto underappreciated role for fibrosis in carcinogenesis. Complex signaling and crosstalk by pathogenic stimuli evoke persistent subclinical inflammation, which in turn, results in a cascade of different cell types, ubiquitous proteins and their corresponding enzymes, cytokine releases, and multiple signaling pathways promoting the onset of fibrosis. There is considerable evidence that the body's attempt to resolve such a modified extracellular environment leads to further disruption of homeostasis and the genesis of the precancerous niche as part of the six-step process that describes carcinogenesis. The precancerous niche is formed and can be understood to develop as a result of (1) pathogenic stimulus, (2) chronic inflammation, and (3) fibrosis with alterations of the extracellular matrix, stromal rigidity, and mechano-transduction. This is why carcinogenesis is not just a process of aberrant cell growth with damaged genetic material but the role of the PCN in its entirety reveals how carcinogenesis can occur without invoking the need for somatic mutations.

scholarly journals 5.1 The Role of Blood Pressure, Aortic Stiffness, and Haemodynamics in Brain Health in Older People with Type 2 Diabetes Mellitus

2020 ◽  
Vol 25 (Supplement 1) ◽  
pp. S37
Author(s):  
Christopher Karayiannis ◽  
Chris Moran ◽  
Richard Beare ◽  
James Sharman ◽  
Thanh Phan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Older People ◽  
Aortic Stiffness ◽  
Brain Health

scholarly journals Emerging role of extracellular vesicles in liver diseases

2019 ◽  
Vol 317 (5) ◽  
pp. G739-G749 ◽  
Author(s):  
Harmeet Malhi
Keyword(s):  
Extracellular Vesicles ◽  
Cell Communication ◽  
Cell Types ◽  
Cell Responses ◽  
Therapeutic Delivery ◽  
Disease States ◽  
Therapeutic Uses ◽  
Potential Biomarker ◽  
Secretion Pathways

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

Role of endothelin receptors in the hypertensive state of kinin B2 knockout mice subjected to a high-salt diet

2002 ◽  
Vol 103 (s2002) ◽  
pp. 380S-384S ◽  
Author(s):  
Isabelle BROCHU ◽  
Julie LABONTÉ ◽  
Ghassan BKAILY ◽  
Pedro D'ORLÉANS-JUSTE
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Tap Water ◽  
Blood Pressure Measurement ◽  
Rna Extraction ◽  
Angiotensin Receptors ◽  
Rt Pcr ◽  
Arterial Blood

Mice with disruption of the kinin B2 receptor (B2KO mice) are sensitive to salt-rich diets, which causes hypertension. The aim of the study was to assess the role of endothelin-1 (ET-1) and angiotensin-II in hypertensive B2KO mice on a salt-rich diet. We also wanted to verify if there is an upregulation of the mRNA expression of the precursors or receptors for these hormones. Two groups of B2KO mice (20–25g) were investigated. The first group received an 8% NaCl diet with 1% NaCl in drinking water (HS) and the second was fed with normal food with tap water (NS). The antagonists tested were the ETA receptor antagonist BQ-123 (1 and 5mg/kg), the ETB receptor antagonist BQ-788 (0.25 and 1mg/kg), the angiotensin receptor type 1 antagonist losartan (10mg/kg) and the angiotensin-converting enzyme inhibitor captopril (3mg/kg). These were injected intraperitoneally 30min prior to blood pressure measurement by the tail-cuff method. We also studied the level of expression of preproET-1, ET-1 receptors, angiotensinogen and angiotensin receptors by RNA extraction from the heart and kidneys of these mice followed by reverse transcriptase (RT)-PCR. B2KO mice (HS) were hypertensive after 8 weeks compared with B2KO mice on normal diet (HS, 93.4±1.5mmHg, n = 7; NS, 61.4±2.7mmHg, n = 7). In the HS group, the mean arterial blood pressure was significantly reduced by BQ-123 (5mg/kg) to 61.9±1.8mmHg (n = 7), by BQ-788 (1mg/kg) to 58.8±2.6mmHg (n = 6), by losartan (10mg/kg) to 73.2±1.7mmHg (n = 8) and by captopril (3mg/kg) to 86.0±2.3mmHg (n = 8). The expression studied by RT-PCR did not show any difference (either in precursors or receptors expression) between hypertensive and normal mice. The four antagonists used seemed to reverse the hypertension. These results suggest that ET-1 and angiotensin-II are probably involved in the mechanism that leads to hypertension since the effect of these hormones is probably not compensated by kinins in B2KO mice. Further studies are necessary to understand the implication of the cross-talk between these hormones in the hypertensive state.

scholarly journals Effects of Blood Pressure on Cognitive Performance in Aging: A Systematic Review

2020 ◽  
Vol 10 (12) ◽  
pp. 919
Author(s):  
Giuseppe Forte ◽  
Maria Casagrande
Keyword(s):  
Blood Pressure ◽  
Cognitive Impairment ◽  
Longitudinal Studies ◽  
Cognitive Performance ◽  
High Blood Pressure ◽  
Pressure Measurement ◽  
Healthy Aging ◽  
Blood Pressure Measurement ◽  
Cross Sectional

Introduction: Cognitive functions play a crucial role in daily functioning. Unfortunately, some cognitive abilities decline in the process of healthy aging. An increasing body of evidence has highlighted the role of lifestyle habits and cardiovascular diseases, such as high blood pressure, in increasing the risk of cognitive decline. Surprisingly, although hypertension is a modifiable risk factor for cerebrovascular damage, the role of hypertension on cognitive impairment development is not still clear. Several key questions remain unresolved, and there are many inconsistent results in studies considering this topic. This review is aimed to systematically analyze the results found by the studies that investigated whether high blood pressure, in both hypertensive and healthy people, is related to cognitive performance. Furthermore, it points to evaluate the role of age in this relationship. Method: The review process was conducted according to the PRISMA statement. Restrictions were made, selecting the studies in English and published in peer-review journals, including at least one cognitive measure and blood pressure measurement. Studies that included participants with medical conditions, dementia, psychiatric disorders, strokes, and brain injury were excluded. Cross-sectional and longitudinal studies were analyzed separately. Finally, blood pressure measured at young life (18–39 years), midlife (age 40–64 years), elderly (65–74 years), and old age (≥75 years) were considered. Results: The review allows 68 studies to be selected, which include 154,935 participants. The results provided evidence of an adverse effect of exposure to high blood pressure on cognitive performance. High blood pressure in midlife was linked with poorer cognitive functioning; this evidence was found in cross-sectional and longitudinal studies. However, this association declines with increasing age and tends to become inconsistent. In older people, the relationship between blood pressure and cognitive performance is non-linear, highlighting a beneficial effect of high blood pressure on cognition. Conclusions: Despite some limitations, this review showed that cardiovascular and neuro-cognitive systems do not operate in isolation, but they are related. Blood pressure can be considered an early biomarker of cognitive impairment, and the necessity of early blood pressure measurement and control was underlined.

scholarly journals Cell to cell hijacking: Role of membrane nanotubes

2022 ◽  
Vol 13 (1) ◽  
pp. 1-2
Author(s):  
Karthikeyan Pethusamy ◽  
Ruby Dhar ◽  
Arun Kumar ◽  
Subhradip Karmakar
Keyword(s):  
Cancer Cells ◽  
Physiological Function ◽  
Cell Communication ◽  
Treatment Resistance ◽  
Cell Types ◽  
Chemotherapy Treatment ◽  
Tunneling Nanotubes ◽  
Membrane Nanotubes ◽  
Membrane Protrusions

Cell to Cell communications is the pivot for life processes. Any event that disrupts this leads to the loss of physiological function, eventually leading to cell death. Evolutionarily, cells developed an elaborate mechanism to undertake this paramount responsibility through cell surface glycocalyx, receptors, integrins, and other recognition molecules. Cells also exchange through local acting soluble mediators as well as through vesicles and exosomes. Recent development in this field led to the identification of a spectacular network of membrane process that seems to be the supremo of all that was known about cellular communications. These are called membrane nanotubes or tunneling nanotubes (TNT). Cellular communication can be subdivided into contact and contactless. The former provides more rapid and molecule transfer as compared to the latter. Tunneling nanotubes (TNTs) are a novel type of contact-based communication. TNTs are straight, thin membrane extensions connecting cells over long distances first reported in PC12 cells in 2004. TNT is believed to form from actin-based membrane protrusion. There are three different models of TNT formation. a>Protrusions from one cell grow and extend until it reaches the other cell, followed by a membrane fusion. b> Membrane protrusions grow from both cells until they meet and establish a connection c> TNT formation by cell dislodgement when cells migrate further apart from each other, and during this movement, TNT is formed. It is possible that all these three models may be operational depending on cell types and context. Tunneling nanotubes (TNT) are dynamic connections between cells, representing a novel route for cell-to-cell communication. TNT was reported in various cell types, like epithelial cells, neuronal cells, mesenchyma cells, and immune cells engaged in intercellular exchanges of molecules, subcellular organelles, and pathogen and viruses transport routes. TNT can extend up to 200 µm in length and about 50 nm to 1500 nm in diameter in macrophages. TNT can be established between similar cell types (homo-TNT) or between one cell type and another ( hetro TNT) and thus may be involved in the initiation and growth of cancer as well as dissemination of cancer cells. TNTs are also assumed to play a role in treatment resistance, e.g., in chemotherapy treatment of cancer. Recently, TNT has been used to hijack mitochondria from healthy cells by the cancer cells as a source of energy. TNT was also reported to transport miRNA and other RNA to the surrounding stroma creating an environment suitable for cancer growth. More research in this discipline is needed to understand the full function of these wonderful nanostructures.

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