In JoVE (1)

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Articles by Hilda Vargas Robles in JoVE

 JoVE Medicine

Analyzing Beneficial Effects of Nutritional Supplements on Intestinal Epithelial Barrier Functions During Experimental Colitis

1Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute, 2Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies of the National Polytechnic Institute, 3Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies of the National Polytechnic Institute

JoVE 55095

Other articles by Hilda Vargas Robles on PubMed

Kidney Function Changes After Acute Exposure to Lead

Proceedings of the Western Pharmacology Society. 2002  |  Pubmed ID: 12434544

The Role of Nitric Oxide in the Post-ischemic Revascularization Process

Pharmacology & Therapeutics. Nov, 2006  |  Pubmed ID: 16950515

Following arterial occlusion, blood vessels respond by sprouting new capillaries (i.e. angiogenesis) and by growing and remodelling pre-existing arterioles into physiologically relevant arteries (i.e. arteriogenesis). The importance of nitric oxide (NO) in ischemia-induced angiogenesis is supported by 4 main findings: (i) the ischemic limb shows an increase in endothelial nitric oxide synthase (eNOS) mRNA, protein expression and NO synthesis; (ii) the absence of the NO pathway (by either pharmacological inhibition or gene disruption of eNOS) abolishes ischemia-induced angiogenesis; (iii) supplementation of NO by the use of exogenous sources restores ischemia-induced angiogenesis; and (iv) cardiovascular diseases associated with decreased NO synthesis show impaired ischemia-induced angiogenesis. Thus, impairment of the NO metabolic pathway could be one of the main contributing factors for the development of peripheral arterial occlusive disease. The restoration of normal NO levels in diseased arteries is therefore a major therapeutic goal; this could be achieved by supplementation with exogenous NO or by strategies designed to increase the concentration of endogenous NO.

Hindlimb Claudication Reflects Impaired Nitric Oxide-dependent Revascularization After Ischemia

Vascular Pharmacology. Jan, 2007  |  Pubmed ID: 17011243

Although vascular remodeling is important in preventing tissue damage and restoring muscle function, there is no evidence of a relationship between vascular remodeling and muscle function after peripheral vascular occlusion. Nitric oxide (NO) has been implicated in the process of vascular remodeling in hindlimb ischemia. Thus, development of alterations in hindlimb gait after ischemia may be associated with impaired nitric oxide-dependent, vascular blood flow recovery. We evaluated hindlimb gait as an index of ischemia-induced revascularization and tested the effects of NO synthase inhibition on both hindlimb blood flow and hindlimb gait locomotion. After 14 days of ischemia, the ischemic hindlimb showed no significant differences in gait locomotion compared to the sham-operated hindlimb. However, hindlimb ischemia drastically reduced hindlimb blood flow from 46+/-3 mL/min/100 g to 12+/-2 mL/min/100 g which reverted to 33+/-5 mL/min/100 g after 14 days of ischemia. eNOS mRNA expression levels at 3, 7, 14, and 28 days after initiation of ischemia, were increased by 50+/-5%, 100+/-10%, 140+/-8% and 270+/-12% respectively and eNOS protein expression levels at 7, 14, and 28 days, were increased by 28+/-3%, 62+/-6% and 80+/-16% respectively. However, eNOS inhibition caused by l-NAME treatment prevented blood flow recovery and correction of abnormal gait locomotion in rats. Thus, the duration of the stride-swing phase increased and the stride length decreased. The knee joint angle decreased during flexion and extension with eNOS inhibition. In conclusion, ischemia-induced revascularization is associated with recovery of both hindlimb blood flow and normal gait locomotion. Moreover, prevention of NO synthesis, a key messenger in ischemia-induced revascularization, is associated with impairment in hindlimb locomotion. Thus, gait locomotion represents a functional model that could be used to evaluate the degree of ischemia-induced revascularization.

Correlation Between Circulating Adhesion Molecule Levels and Albuminuria in Type 2 Diabetic Normotensive Patients

Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. Aug, 2007  |  Pubmed ID: 17660723

Endothelial dysfunction is a common feature in type 2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules, and urinary albumin excretion. The aim of this study was to evaluate the role of circulating soluble adhesion molecules in the development of albuminuria.

Lead Exposure Effect on Angiotensin II Renal Vasoconstriction

Human & Experimental Toxicology. Jun, 2007  |  Pubmed ID: 17698945

Low levels of chronic lead exposure can produce hypertension and endothelial dysfunction, which could be associated with oxidative stress, changes in vascular tone and an imbalance of endothelial-derived vasoconstriction and vasodilator factors. The aim was to investigate the effect of chronic lead-exposure on angiotensin II-induced vasoconstriction in isolated perfused kidney and microvessels. Male Wistar rats (230-250 g) were treated for 12 weeks with lead acetate (100 ppm, Pbgroup) or pure water (control group). We evaluated the vascular reactivity in the kidneys and renal microvessels in the presence and absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) in both groups. The nitrite concentration in renal perfusate was measured as an index of NO released, renal abundance of 3-nitrotyrosine was measured as well as endothelial NO synthase (eNOS) expression. Oxidative stress was measured by using the oxidative fluorescence dye dihydroethidium (DHE) to evaluate in situ production of superoxide and identified by confocal microscopy. Lead-exposure significantly increased blood pressure, eNOS protein expression, oxidative stress and vascular reactivity to angiotensin II. L-NAME potentiated vascular response to angiotensin II in control group but had no effect on the Pb-group. Nitrites released from the kidney of lead-group was lower compared to the control group while 3-nitrotyrosine was higher. This data suggest that lead-induced hypertension could be caused partially by an altered NOsystem.

Nitric Oxide-dependent Neovascularization Role in the Lower Extremity Disease

Current Pharmaceutical Design. 2007  |  Pubmed ID: 18220796

Peripheral arterial occlusive disease (PAD) describes vascular disorders associated with ischemia and PAD affects about 8 million people in the United States. Moreover, PAD's prevalence can increase dramatically if cardiovascular disease is present. In healthy individuals reducing blood flow through the lower extremity is followed by a physiological process to limit ischemia in the distal tissue. This process is called revascularization and impairing revascularization results in PAD. Studies suggest nitric oxide (NO) maybe involved in the ischemia-dependent hindlimb revascularization process. NO is increased in the ischemic hindlimb and eliminating NO impairs the revascularization process. Moreover, restoring NO improves hindlimb revascularization. NO may be acting through its effects on vascular tone, cell migration, or extracellular matrix degradation. The present review illustrates nitric oxide's critical role in the ischemia-induced hindlimb revascularization. Thus, restoring normal NO levels in diseased arteries may represent a viable therapeutic avenue by supplementing exogenous NO or employing therapeutic strategies to either increase NO synthesis and its messengers or decrease NO catabolism.

Kidney Damage After Renal Ablation is Worsened in Endothelial Nitric Oxide Synthase -/- Mice and Improved by Combined Administration of L-arginine and Antioxidants

Nephrology (Carlton, Vic.). Jun, 2008  |  Pubmed ID: 18315704

Reduction in nitric oxide (NO) levels during kidney failure has been related to the reaction of NO with superoxide anions to yield peroxynitrite which possesses the biological activity responsible for renal damage. However, stimulation of the NO pathway ameliorates the progression of kidney failure. Thus, it is unclear whether NO prevents or acts as the compound responsible for the cytotoxicity observed during kidney failure.

[Levels of Soluble Adhesion Molecules Among Normal and Hypertensive Type 2 Diabetic Patients]

Gaceta Medica De Mexico. Jan-Feb, 2008  |  Pubmed ID: 18619052

Hypertension and type-2 diabetes affect endothelial function, which in turn increases the expression of soluble adhesion molecules and lead to the development of vascular damage. The aim of this study was to assess soluble adhesion molecule levels among normotensive and hypertensive diabetic patients.

The Effect of Trandolapril and Its Fixed-dose Combination with Verapamil on Circulating Adhesion Molecules Levels in Hypertensive Patients with Type 2 Diabetes

Clinical and Experimental Hypertension (New York, N.Y. : 1993). Oct, 2008  |  Pubmed ID: 18855271

Endothelial dysfunction in hypertensive type-2 diabetic patients is associated with increased levels of circulating soluble adhesion molecules (SAM). SAM participate in the development of diabetic macroangiopathy and microangiopathy. The aim of this study was to compare the effect of trandolapril (T) and its fixed-dose combination with verapamil (FDTV) on SAM levels in hypertensive type-2 diabetic patients.

Correlation Between Circulating Adhesion Molecule Levels and Albuminuria in Type-2 Diabetic Hypertensive Patients

Kidney & Blood Pressure Research. 2009  |  Pubmed ID: 19342863

Endothelial dysfunction, a common feature among hypertensive and type-2 diabetic patients, is associated with inflammation, increased levels of circulating soluble adhesion molecules (SAM), and urinary albumin excretion. The aim of this study was to evaluate the role of circulating SAM levels in the development of albuminuria in hypertensive type-2 diabetic patients.

Correlation Between the Levels of Circulating Adhesion Molecules and Atherosclerosis in Type-2 Diabetic Normotensive Patients: Circulating Adhesion Molecules and Atherosclerosis

Cell Adhesion & Migration. Oct-Dec, 2009  |  Pubmed ID: 19717975

Endothelial dysfunction is a common feature in type-2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules and atherosclerosis. The aim of this study was to evaluate the relationship between the levels of circulating soluble adhesion molecules and the degree of atherosclerosis in normotensive type-2 diabetic patients.

L-arginine and Antioxidant Diet Supplementation Partially Restores Nitric Oxide-dependent Regulation of Phenylephrine Renal Vasoconstriction in Diabetics Rats

Journal of Renal Nutrition : the Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. May, 2010  |  Pubmed ID: 20097580

The increase of reactive oxygen species (ROS) in diabetes potentiates the vascular effects of phenylephrine through nitric oxide (NO) impairment, facilitating the development of diabetic nephropathy. We propose that the combination of an antioxidant and L-arginine as diet supplements could prevent the increased vascular response to phenylephrine in diabetic animals.

Effect of Phlorizin on SGLT2 Expression in the Kidney of Diabetic Rats

Journal of Nephrology. Sep-Oct, 2010  |  Pubmed ID: 20349407

The purpose of our study was to determine whether increased SGLT2 expression in the kidney of diabetic rats was associated with the development of hypertension and to investigate the effect of phlorizin (P) on blood pressure and SGLT2 expression in diabetic rats.

Correlation Between the Levels of Circulating Adhesion Molecules and Atherosclerosis in Hypertensive Type-2 Diabetic Patients

Clinical and Experimental Hypertension (New York, N.Y. : 1993). 2010  |  Pubmed ID: 20662732

Endothelial dysfunction is a common feature in type-2 diabetic patients and in hypertension, and is associated with inflammation, increased levels of circulating soluble adhesion molecules, and atherosclerosis. The aim of this study was to evaluate the relationship between the levels of circulating soluble adhesion molecules and the degree of atherosclerosis in hypertensive type-2 diabetic patients. We studied 30 hypertensive type-2 diabetic patients in whom VCAM-1, ICAM-1, and E-selectin were measured by ELISA. Additionally, the intimal-medial thickness of both the common and internal carotid arteries was measured (B-mode ultrasound). The levels of circulating adhesion molecules and maximal carotid artery intimal-medial thicknesses were correlated using the Spearman correlation coefficient test. Statistical analysis was performed with ANOVA. We found significant correlations between ICAM-1 (r = 0.5) levels and maximal carotid artery intimal-medial thickness these patients. No correlation was observed with E-selectin and VCAM-1. Our results suggest that ICAM-1 is associated and correlated with the degree of atherosclerosis in type-2 diabetic hypertensive patients.

Is Tetrahydrobiopterin a Therapeutic Option in Diabetic Hypertensive Patients?

Integrated Blood Pressure Control. 2010  |  Pubmed ID: 21949628

Nitric oxide (NO) is an important regulator of vascular tone, and is also an antithrombotic, anti-inflammatory, antiproliferative, and antiatherogenic factor. Endothelial function is altered in patients with coronary artery disease, stroke, and peripheral artery disease, and endothelial dysfunction correlates with the risk factor profile for a patient. Hypertension and type 2 diabetes are risk factors for vascular disease, and are both pathologies characterized by loss of NO activity. Indeed, endothelial dysfunction is usually present in diabetic and/or hypertensive patients. Tetrahydrobiopterin is an essential cofactor for the NO synthase enzyme, and insufficiency of this cofactor leads to uncoupling of the enzyme, release of superoxide, endothelial dysfunction, progression of hypertension, and finally, proatherogenic effects. Tetrahydrobiopterin is also an important mediator of NO synthase regulation in type 2 diabetes and hypertension, and may be a rational therapeutic target to restore endothelial function and prevent vascular disease in these patients. The aim of this paper is to review the rationale for therapeutic strategies directed to biopterins as a target for vascular disease in type 2 diabetic hypertensive patients.

Correlation Between Circulating Adhesion Molecules and Resistin Levels in Hypertensive Type-2 Diabetic Patients

Inflammation & Allergy Drug Targets. Feb, 2011  |  Pubmed ID: 21184654

Endothelial dysfunction, a common feature among hypertensive and type-2 diabetic patients, has been associated with inflammation and increased concentrations of serum soluble adhesion molecules and resistin, a monocyte-macrophage- and adipocyte-derived cytokine.

Prevention of Renal Injury and Endothelial Dysfunction by Chronic L-arginine and Antioxidant Treatment

Renal Failure. 2011  |  Pubmed ID: 21219205

We evaluated the effects of vitamins with antioxidant properties (a combination of vitamins C and E) and L-arginine treatment on renal failure in mice by measuring survival rate. The molecular changes were elucidated by determining endothelial tetrahydrobiopterin (BH4) levels and nitric oxide synthase (eNOS) mRNA expression in mice with renal ablation. Previous studies have shown that endothelial dysfunction in 5/6 nephrectomized mice is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. WTC57 mice were divided into three groups: Group 1 was the sham-operated group (C); Group 2 was the 5/6 nephrectomized group (Nfx); and Group 3 was a group of 5/6 nephrectomized mice, treated with L-arginine and vitamins with antioxidant properties (NfxTx; 200 mg/kg L-arginine, 83 mg/kg vitamin C, and 46.6 mg/kg vitamin E). After 20 weeks of treatment, urinary protein excretion, blood pressure, BH4 and dihydrobiopterin (BH2) levels, eNOS mRNA, oxidative stress, and survival rate were determined. An increase in urinary protein excretion, blood pressure, and oxidative stress was prevented in the NfxTx group, but not in the Nfx group. BH4 and eNOS mRNA expression was increased by 32% and 78%, respectively, in the NfxTx group. Furthermore, the treatment increased the survival rate by 33%. Our results indicate that under normal conditions, NO appears to protect renal function. However, this NO-dependent protection is lost during kidney failure, probably due to increased reactive oxygen species synthesis. The treatment restores the viability of NO and prevents the BH4 oxidation. Therefore, this treatment may represent a therapeutic approach for the management of kidney disease.

Relationship Between Angiotensin II Receptor Expression and Cardiovascular Risk Factors in Mexican Patients with Coronary Occlusive Disease

Experimental and Molecular Pathology. Aug, 2011  |  Pubmed ID: 21596033

The density of Angiotensin II (Ang) receptors on tissue surfaces is regulated by multiple hormones, cytokines and metabolic factors and is profoundly affected by various pathological conditions, such as age, diet and environmental conditions. The participation of several cardiovascular risk factors in the regulation of Angiotensin II receptor expression has been incompletely studied. We performed an ex-vivo study with human aortic postsurgical specimens to test the hypothesis that Ang AT1 and AT2 receptor expression in human aortic arteries is associated with the presence of cardiovascular risk factors. We included 31 Mexican patients with coronary artery disease. We evaluated Angiotensin II receptor expression by immunostaining and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphisms by polymerase chain reaction. AT1 and AT2 receptor expression was increased in the aortic segments from the cardiovascular patients compared with control arteries and in patients with the DD genotype. There was a correlation between increased AT1 receptor expression and the number of cardiovascular risk factors present in the patient. Furthermore, reduction of AT1 expression correlated with the number of drug combinations used in the patients. These correlations were not present with respect to AT2 receptor expression. We suggest that increased AT1 receptor expression is associated with the DD genotype. Thus the presence of several cardiovascular risk factors as well as DD genotype, induce AT1 expression increasing the probability to develop coronary occlusive disease.

Impact of Trandolapril Therapy and Its Combination with a Calcium Channel Blocker on Plasma Adiponectin Levels in Patients with Type 2 Diabetes and Hypertension

Therapeutic Advances in Cardiovascular Disease. Aug, 2011  |  Pubmed ID: 21737486

Adiponectin is secreted from adipose tissue and exhibits a protective effect against cardiovascular disease; plasma adiponectin concentrations are decreased in type 2 diabetic and in hypertensive patients.

Cyclooxygenase-2 and Kidney Failure

Prostaglandins & Other Lipid Mediators. Aug, 2012  |  Pubmed ID: 22119250

Cyclooxygenase (COX)-dependent prostaglandins are necessary for normal kidney function. These prostaglandins are associated with inflammation, maintenance of sodium and water homeostasis, control of renin release, renal vasodilation, vasoconstriction attenuation, and prenatal renal development. COX-2 expression is regulated by the renin-angiotensin system, glucocorticoids or mineralcorticoids, and aldosterone, supporting a role for COX-2 in kidney function. Indeed, COX-2 mRNA and protein levels as well as enzyme activity are increased, along with PGE2, during kidney failure. In addition, changes in COX-2 expression are associated with increased blood pressure, urinary volume, sodium and protein and decreased urinary osmolarity. Intrarenal mechanisms such as angiotensin II (Ang II) production, increased sodium delivery, glomerular hypertension, and renal tubular inflammation have been suggested to be responsible for the increase in COX-2 expression. Although, specific COX-2 pharmacological inhibition has been related to the prevention of kidney damage, clinical studies have reported that COX-2 inhibition may cause side effects such as edema or a modest elevation in blood pressure and could possibly interfere with antihypertensive drugs and increase the risk of cardiovascular complications. Thus, administration of COX-2 inhibitors requires caution, especially in the presence of underlying cardiovascular disease.

Association Between the Levels of Circulating Adhesion Molecules and Biopterins in Type-2 Diabetic Normotensive Patients Adhesion Molecules and Biopterins

Endocrine, Metabolic & Immune Disorders Drug Targets. Sep, 2012  |  Pubmed ID: 22497223

Endothelial dysfunction is a common feature in type-2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules and atherosclerosis. Insufficiency of tetrahydrobiopterin leads to uncoupling of the nitric oxide synthase enzyme an endothelial dysfunction.

Endothelial Nitric Oxide Synthase Impairment is Restored by Clofibrate Treatment in an Animal Model of Hypertension

European Journal of Pharmacology. Jun, 2012  |  Pubmed ID: 22542661

Adequate production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) requires eNOS coupling promoted by tetrahydrobiopterin (BH(4)). Under pathological conditions such as hypertension, BH(4) is diminished, avoiding eNOS coupling. When eNOS is "uncoupled", it yields a superoxide anion instead of NO. Peroxisome proliferator activated receptors (NR1C) are a family of nuclear receptors activated by ligand. Clofibrate, a member of a hypolipidemic class of drugs, acts by activating the alpha isoform of NR1C. To determine the participation of NR1C1 activation in BH(4) and dihydrobiopterin (BH(2)) metabolism and its implications on eNOS coupling in hypertension, we performed aortic coarctation (AoCo) at inter-renal level on male Wistar rats in order to have a hypertensive model. Rats were divided into the following groups: Sham+vehicle (Sham-V); AoCo+vehicle (AoCo-V); Sham+clofibrate (Sham-C), and AoCo+clofibrate (AoCo-C). Clofibrate (7 days) increased eNOS coupling in the AoCo-C group compared with AoCo-V. Clofibrate also recovered the BH(4):BH(2) ratio in control values and prevented the rise in superoxide anion production, lipoperoxidation, and reactive oxygen species production. In addition, clofibrate increased GTP cyclohydrolase-1 (GTPCH-1) protein expression, which is related with BH(4) recovered production. NR1C1 stimulation re-establishes eNOS coupling, apparently through recovering the BH(4):BH(2) equilibrium and diminishing oxidative stress. Both can contribute to high blood pressure attenuation in hypertension secondary to AoCo.

Beneficial Effect of Combination Therapy Using an Angiotensin-converting Enzyme Inhibitor Plus Verapamil on Circulating Resistin Levels in Hypertensive Patients with Type 2 Diabetes

Experimental and Clinical Cardiology. 2012  |  Pubmed ID: 23592936

Resistin levels are strongly correlated with insulin resistance and vascular inflammation. Type 2 diabetic and hypertensive patients have higher circulating levels of resistin, which is associated with endothelial dysfunction.

Correlation Between Levels of Circulating Adipokines and Adiponectin/resistin Index with Carotid Intima-media Thickness in Hypertensive Type 2 Diabetic Patients

Cardiology. 2013  |  Pubmed ID: 23736118

Hypoadiponectinemia and hyperresistinemia are associated with cardiovascular disease. The increase in the carotid intima-media thickness (CIMT) assessed by B-mode ultrasound has been directly associated with increased risk of myocardial infarction and stroke.

Small GTPases of the Ras Superfamily Regulate Intestinal Epithelial Homeostasis and Barrier Function Via Common and Unique Mechanisms

Tissue Barriers. Dec, 2013  |  Pubmed ID: 24868497

The intestinal epithelium forms a stable barrier protecting underlying tissues from pathogens in the gut lumen. This is achieved by specialized integral membrane structures such as tight and adherens junctions that connect neighboring cells and provide stabilizing links to the cytoskeleton. Junctions are constantly remodeled to respond to extracellular stimuli. Assembly and disassembly of junctions is regulated by interplay of actin remodeling, endocytotic recycling of junctional proteins, and various signaling pathways. Accumulating evidence implicate small G proteins of the Ras superfamily as important signaling molecules for the regulation of epithelial junctions. They function as molecular switches circling between an inactive GDP-bound and an active GTP-bound state. Once activated, they bind different effector molecules to control cellular processes required for correct junction assembly, maintenance and remodelling. Here, we review recent advances in understanding how GTPases of the Rho, Ras, Rab and Arf families contribute to intestinal epithelial homeostasis.

Correlation Between Biopterin Levels and Intimal-media Thickness in Type-2 Diabetic Hypertensive Patients

Journal of Diabetes and Metabolic Disorders. Jan, 2014  |  Pubmed ID: 24393252

Biopterins have a crucial role in the function of nitric oxide synthase, uncoupling of the enzyme leads to endothelial dysfunction and vascular damage, The aim of this study was to evaluate the relationship between the levels of biopterins with carotid intima-media thickness (CIMT) in hypertensive type-2 diabetic patients.

Early Stage of Obesity Potentiates Nitric Oxide Reduction During the Development of Renal Failure

Journal of Nephrology. Jun, 2014  |  Pubmed ID: 24446346

Obesity is a serious health problem associated with the pathogenesis of various metabolic diseases. Nitric Oxide (NO) plays an important role in kidney function and altered NO levels have been associated with the pathogenesis of obesity. Therefore, we aimed to study whether an early stage of obesity contributes with progression of renal failure through further NO impairment.

The Role of Actin-binding Proteins in the Control of Endothelial Barrier Integrity

Thrombosis and Haemostasis. Jan, 2015  |  Pubmed ID: 25183310

The endothelial barrier of the vasculature is of utmost importance for separating the blood stream from underlying tissues. This barrier is formed by tight and adherens junctions (TJ and AJ) that form intercellular endothelial contacts. TJ and AJ are integral membrane structures that are connected to the actin cytoskeleton via various adaptor molecules. Consequently, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. While a circumferential cortical actin ring stabilises junctions, the formation of contractile stress fibres, e. g. under inflammatory conditions, can contribute to junction destabilisation. However, the role of actin-binding proteins (ABP) in the control of vascular permeability has long been underestimated. Naturally, ABP regulate permeability via regulation of actin remodelling but some actin-binding molecules can also act independently of actin and control vascular permeability via various signalling mechanisms such as activation of small GTPases. Several studies have recently been published highlighting the importance of actin-binding molecules such as cortactin, ezrin/radixin/moesin, Arp2/3, VASP or WASP for the control of vascular permeability by various mechanisms. These proteins have been described to regulate vascular permeability under various pathophysiological conditions and are thus of clinical relevance as targets for the development of treatment strategies for disorders that are characterised by vascular hyperpermeability such as sepsis. This review highlights recent advances in determining the role of ABP in the control of endothelial cell contacts and vascular permeability.

Antioxidative Diet Supplementation Reverses High-fat Diet-induced Increases of Cardiovascular Risk Factors in Mice

Oxidative Medicine and Cellular Longevity. 2015  |  Pubmed ID: 25922641

Obesity is a worldwide epidemic that is characterized not only by excessive fat deposition but also by systemic microinflammation, high oxidative stress, and increased cardiovascular risk factors. While diets enriched in natural antioxidants showed beneficial effects on oxidative stress, blood pressure, and serum lipid composition, diet supplementation with synthetic antioxidants showed contradictive results. Thus, we tested in C57Bl/6 mice whether a daily dosage of an antioxidative mixture consisting of vitamin C, vitamin E, L-arginine, eicosapentaenoic acid, and docosahexaenoic acid (corabion) would affect cardiovascular risk factors associated with obesity. Obese mice showed increased serum triglyceride and glucose levels and hypertension after eight weeks of being fed a high-fat diet (HFD). Importantly, corabion ameliorated all of these symptoms significantly. Oxidative stress and early signs of systemic microinflammation already developed after two weeks of high-fat diet and were significantly reduced by daily doses of corabion. Of note, the beneficial effects of corabion could not be observed when applying its single antioxidative components suggesting that a combination of various nutrients is required to counteract HFD-induced cardiovascular risk factors. Thus, daily consumption of corabion may be beneficial for the management of obesity-related cardiovascular complications.

Oxidative Stress-Dependent Coronary Endothelial Dysfunction in Obese Mice

PloS One. 2015  |  Pubmed ID: 26381906

Obesity is involved in several cardiovascular diseases including coronary artery disease and endothelial dysfunction. Endothelial Endothelium vasodilator and vasoconstrictor agonists play a key role in regulation of vascular tone. In this study, we evaluated coronary vascular response in an 8 weeks diet-induced obese C57BL/6 mice model. Coronary perfusion pressure in response to acetylcholine in isolated hearts from obese mice showed increased vasoconstriction and reduced vasodilation responses compared with control mice. Vascular nitric oxide assessed in situ with DAF-2 DA showed diminished levels in coronary arteries from obese mice in both basal and acetylcholine-stimulated conditions. Also, released prostacyclin was decreased in heart perfusates from obese mice, along with plasma tetrahydrobiopterin level and endothelium nitric oxide synthase dimer/monomer ratio. Obesity increased thromboxane A2 synthesis and oxidative stress evaluated by superoxide and peroxynitrite levels, compared with control mice. Obese mice treated with apocynin, a NADPH oxidase inhibitor, reversed all parameters to normal levels. These results suggest that after 8 weeks on a high-fat diet, the increase in oxidative stress lead to imbalance in vasoactive substances and consequently to endothelial dysfunction in coronary arteries.

Experimental Colitis Is Attenuated by Cardioprotective Diet Supplementation That Reduces Oxidative Stress, Inflammation, and Mucosal Damage

Oxidative Medicine and Cellular Longevity. 2016  |  Pubmed ID: 26881044

Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are multifactorial, relapsing disorders of the gastrointestinal tract. However, the etiology is still poorly understood but involves altered immune responses, epithelial dysfunction, environmental factors, and nutrition. Recently, we have shown that the diet supplement corabion has cardioprotective effects due to reduction of oxidative stress and inflammation. Since oxidative stress and inflammation are also prominent risk factors in IBD, we speculated that corabion also has beneficial effects on experimental colitis. Colitis was induced in male mice by administration of 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 3 or 7 days with or without daily gavage feeding of corabion consisting of vitamin C, vitamin E, L-arginine, and eicosapentaenoic and docosahexaenoic acid. We found that corabion administration attenuated DSS-induced colon shortening, tissue damage, and disease activity index during the onset of colitis. Mechanistically, these effects could be explained by reduced neutrophil recruitment, oxidative stress, production of proinflammatory cytokines, and internalization of the junctional proteins ZO-1 and E-cadherin leading to less edema formation. Thus, corabion may be a useful diet supplement for the management of chronic inflammatory intestinal disorders such as IBD.

Loss of Cortactin Causes Endothelial Barrier Dysfunction Via Disturbed Adrenomedullin Secretion and Actomyosin Contractility

Scientific Reports. Jun, 2016  |  Pubmed ID: 27357373

Changes in vascular permeability occur during inflammation and the actin cytoskeleton plays a crucial role in regulating endothelial cell contacts and permeability. We demonstrated recently that the actin-binding protein cortactin regulates vascular permeability via Rap1. However, it is unknown if the actin cytoskeleton contributes to increased vascular permeability without cortactin. As we consistently observed more actin fibres in cortactin-depleted endothelial cells, we hypothesised that cortactin depletion results in increased stress fibre contractility and endothelial barrier destabilisation. Analysing the contractile machinery, we found increased ROCK1 protein levels in cortactin-depleted endothelium. Concomitantly, myosin light chain phosphorylation was increased while cofilin, mDia and ERM were unaffected. Secretion of the barrier-stabilising hormone adrenomedullin, which activates Rap1 and counteracts actomyosin contractility, was reduced in plasma from cortactin-deficient mice and in supernatants of cortactin-depleted endothelium. Importantly, adrenomedullin administration and ROCK1 inhibition reduced actomyosin contractility and rescued the effect on permeability provoked by cortactin deficiency in vitro and in vivo. Our data suggest a new role for cortactin in controlling actomyosin contractility with consequences for endothelial barrier integrity.

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