Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways

2014 ◽  
Vol 128 (7) ◽  
pp. 411-423 ◽  
Author(s):  
Thiago Bruder-Nascimento ◽  
Glaucia E. Callera ◽  
Augusto C. Montezano ◽  
Ying He ◽  
Tayze T. Antunes ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Vascular Injury ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction

Our data identify putative molecular mechanisms involving Rac1/2-sensitive, NADPH oxidase (Nox)-dependent pathways, whereby statins may protect against vascular dysfunction in diabetes.

scholarly journals A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Zhang ◽  
Christopher D. Kontos ◽  
Brian H. Annex ◽  
Aleksander S. Popel
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Reaction Network ◽  
Vascular Growth ◽  
Downstream Signaling ◽  
Signaling Axis ◽  
Agonistic Activity ◽  
Molecular Regulatory Mechanisms

AbstractThe Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

scholarly journals Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis

2015 ◽  
Vol 308 (4) ◽  
pp. G298-G312 ◽  
Author(s):  
Diptadip Dattaroy ◽  
Sahar Pourhoseini ◽  
Suvarthi Das ◽  
Firas Alhasson ◽  
Ratanesh Kumar Seth ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Nonalcoholic Steatohepatitis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Micro Rna ◽  
Protein Levels ◽  
Significant Research ◽  
Human Livers

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.

scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

2017 ◽  
Vol 234 (1) ◽  
pp. T67-T82 ◽  
Author(s):  
Jennifer J DuPont ◽  
Iris Z Jaffe
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Kidney Injury ◽  
Vascular Pathology ◽  
The Impact

Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality.

scholarly journals Nox2 Deficiency Prevents Hypertension-Induced Vascular Dysfunction and Hypertrophy in Cerebral Arterioles

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Siu-Lung Chan ◽  
Gary L. Baumbach
Keyword(s):  
Nadph Oxidase ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Cross Sectional ◽  
Cranial Window ◽  
Cerebral Arterioles ◽  
The Right ◽  
The Brain

Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were givenNG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levelsex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y  mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide.

scholarly journals Healthberry 865® and Its Related, Specific, Single Anthocyanins Exert a Direct Vascular Action, Modulating Both Endothelial Function and Oxidative Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1191
Author(s):  
Albino Carrizzo ◽  
Rosario Lizio ◽  
Paola Di Pietro ◽  
Michele Ciccarelli ◽  
Antonio Damato ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Intracellular Signaling ◽  
Vascular Reactivity ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Epidemiological Studies ◽  
Direct Role ◽  
And Oxidative Stress

In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.

Increased Oxidative Stress In Sickle Cell Disease Activates The Renin-Angiotensin-TGF-β Pathway To Mediate Sickle Nephropathy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2211-2211 ◽  
Author(s):  
Swarnava Roy ◽  
Diamantis G. Konstantinidis ◽  
Tilat Rizvi ◽  
Kyung-Hee Chang ◽  
Nambirajan Sundaram ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Nadph Oxidase ◽  
Sickle Cell ◽  
Molecular Mechanisms ◽  
Ras Signaling ◽  
Cell Disease ◽  
Renin Angiotensin ◽  
Urine Concentrating Ability

Abstract Sickle nephropathy (SN) is a common cause of morbidity and mortality in sickle cell disease (SCD), begins with hyposthenuria in childhood, and progresses to albuminuria, focal sclerosing glomerulo-sclerosis (FSGS), glomerular hypofiltration, and end stage renal disease in 30-50% adults The precise molecular mechanisms underlying SN are largely unexplored, as SN has been presumed to result from sickling associated ischemia/necrosis. Herein, we explored mechanisms of sickle renal pathologies utilizing the Berkeley sickle mouse model (HbS mice). We show that HbS mice develop renal pathologies similar to human SN, with hyposthenuria, progressive albuminuria, FSGS and nephron loss. HbS mice 4-8 weeks of age have high GFR compared to WT mice, that rapidly declines to subnormal levels by 16-24 weeks of age. We next explored the role of increased oxidant stress in mediating SN. We recently showed that sickle RBC are likely major contributors of reactive oxygen species (ROS) in SCD, and these high levels of ROS in RBC are also generated enzymatically by NADPH oxidase (George, et al Blood 2013). We now show that SCD-associated ROS initiate pathologically significant processes, including increased conversion of oxidized angiotensinogen (ANG) to angiotensin II (AT), and secondary AT receptor 1 (AT1R)-mediated generation of TGFβ1 in the HbS kidneys, which then phosphorylates Smad 2/3. We tested if activated Renin-Angiotensin-system (RAS) -AT1R-mediated TGFβ1 signaling causes albuminuria and FSGS in HbS mice. We blocked the AT1R with losartan, or its ligand AT by an angiotensin converting enzyme inhibitor, Captopril, starting at an early age (4wk) for 6-12 months. This prevented albuminuria and FSGN development in HbS mice. However, sickle hyposthenuria was worsened with losartan, and was even more severe with captopril. These data suggest that excessive AT1R signaling causes sickle glomerulopathy, and AT1R promotes urine concentrating ability; however, the captopril effect suggests that AT binds another receptor to further mediate urine concentrating ability. Increased RAS signaling is known to mediate glomerulopathy in other diseases, but its role in urine concentration has not been described. AT can also bind AT2 receptor that has been identified as a renoprotective receptor. We therefore investigated the role of AT1R and AT2R in sickle glomerulopathy and hyposthenuria by transplanting bone marrow from HbS mice into WT mice, AT1R-/- mice (HbS/AT1R-/-) and AT2R-/- mice (HbS/AT2R-/-) and followed them for 6-12 months. Bone marrow from WT mice was concurrently transplanted into WT, AT1R and AT2R deficient mice as controls. HbS/WT mice developed similar SN as in HbS mice with progressive albuminuria and hyposthenuria, the former reversible with losartan and captopril, and the latter worsened by these drugs as described above. However, HbS/AT1R mice were protected from development of albuminuria and FSGS, had reduced active TGFβ1 and PSmad-2/3, unlike HbS/WT mice, but developed significant hyposthenuria, which was worse than HbS/WT mice, and reminiscent of the effect of losartan. The HbS/AT2R mice also developed significantly worse hyposthenuria than HbS/WT mice, and were additionally not protected from albuminuria. These data suggest both AT1R and AT2R mediate urine concentrating ability, an effect blocked more effectively by captopril than losartan. AT1R signaling is known to activate NADPH oxidase to generate ROS. Indeed, mice placed on Captopril and Losartan had reduced ROS in RBC and platelets (cell types known to express AT1R) and kidneys, and consequently reduced RAS activation (significantly less oxidized ANG and AT), breaking the ROS-RAS-AT1R feedback loop. Significantly higher RBC and platelet ROS, oxidized ANG, and AT levels were also confirmed in patients with SCD as compared to their unaffected sibling controls. In summary, our data show that SN occurs from two distinct mechanisms – a) glomerulopathy that results in albuminuria, glomerulosclerosis and renal failure, which occurs primarily from increased AT1R signaling, and b) a tubulopathy, that results in inability to concentrate urine, and is worsened by AT1R signaling blockade, and AT2R signaling protects tubules against worsening hyposthenuria. Targeted therapies that block AT1R signaling but increase AT2R signaling may improve both glomerular and tubular pathologies in SCD and can now be explored. Disclosures: No relevant conflicts of interest to declare.

The role of TRAF3IP2 in obesity-associated vascular insulin resistance and dysfunction

2020 ◽  
Author(s):  
◽  
Zachary I. Grunewald
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Vascular Dysfunction ◽  
Reactive Hyperemia ◽  
Causal Role ◽  
Wild Type ◽  
Vascular Control

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI-COLUMBIA AT REQUEST OF AUTHOR.] Insulin resistance in the vasculature is a characteristic feature of obesity and contributes to the pathogenesis of vascular dysfunction and disease. However, the molecular mechanisms underlying obesity-associated vascular insulin resistance and dysfunction remain poorly understood. We hypothesized that TRAF3 Interacting Protein 2 (TRAF3IP2), a pro-inflammatory adaptor molecule known to activate pathological stress pathways and implicated in cardiovascular disease, plays a causal role in obesity-associated vascular insulin resistance and dysfunction. We tested this hypothesis by employing genetic-manipulation in endothelial cells in vitro and in isolated arteries ex vivo, and by using a mouse model of TRAF3IP2 ablation and diet-induced obesity in vivo. We show that forced expression of TRAF3IP2 blunts insulin signaling in endothelial cells and diminishes endothelium-dependent vasorelaxation in isolated aortic rings. Further, 16 weeks of high fructose/high sucrose (HFHS) feeding impaired glucose tolerance, aortic insulin-induced vasorelaxation, and hindlimb postocclusive reactive hyperemia, while increasing blood pressure and arterial stiffness in wild-type male mice. Notably, TRAF3IP2 gene ablation protected mice against such metabolic and vascular defects caused by HFHS feeding. Interestingly, wild-type female mice expressed markedly reduced levels of TRAF3IP2 mRNA independent of diet and were protected against HFHS diet-induced vascular dysfunction. These data indicate that TRAF3IP2 plays a causal role in vascular insulin resistance and dysfunction. Specifically, the present findings highlight a sexual dimorphic role of TRAF3IP2 in vascular control and identify it as a promising therapeutic target in vasculometabolic derangements associated with obesity, particularly in males.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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