scholarly journals Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Satomi Kagota ◽  
Kana Maruyama ◽  
John J. McGuire
Keyword(s):  
Systematic Review ◽  
Metabolic Syndrome ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cell Surface Receptor ◽  
Metabolic Dysfunction ◽  
The Face ◽  
Surface Receptor ◽  
Treatment Of Obesity

Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats. We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study.

scholarly journals Context-dependent effects of SOCS3 in angiotensin II-induced vascular dysfunction and hypertension in mice: mechanisms and role of bone marrow-derived cells

2016 ◽  
Vol 311 (1) ◽  
pp. H146-H156 ◽  
Author(s):  
Ying Li ◽  
Dale A. Kinzenbaw ◽  
Mary L. Modrick ◽  
Lecia L. Pewe ◽  
Frank M. Faraci
Keyword(s):  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Carotid Artery Disease ◽  
Vascular Dysfunction ◽  
Cytokine Signaling ◽  
Ang Ii ◽  
Direct Effects ◽  
Bone Marrow Derived Cells

Carotid artery disease is a major contributor to stroke and cognitive deficits. Angiotensin II (Ang II) promotes vascular dysfunction and disease through mechanisms that include the IL-6/STAT3 pathway. Here, we investigated the importance of suppressor of cytokine signaling 3 (SOCS3) in models of Ang II-induced vascular dysfunction. We examined direct effects of Ang II on carotid arteries from SOCS3-deficient (SOCS3+/−) mice and wild-type (WT) littermates using organ culture and then tested endothelial function with acetylcholine (ACh). A low concentration of Ang II (1 nmol/l) did not affect ACh-induced vasodilation in WT but reduced that of SOCS3+/−mice by ∼50% ( P < 0.05). In relation to mechanisms, effects of Ang II in SOCS3+/−mice were prevented by inhibitors of STAT3, IL-6, NF-κB, or superoxide. Systemic Ang II (1.4 mg/kg per day for 14 days) also reduced vasodilation to ACh in WT. Surprisingly, SOCS3 deficiency prevented most of the endothelial dysfunction. To examine potential underlying mechanisms, we performed bone marrow transplantation. WT mice reconstituted with SOCS3+/−bone marrow were protected from Ang II-induced endothelial dysfunction, whereas reconstitution of SOCS3+/−mice with WT bone marrow exacerbated Ang II-induced effects. The SOCS3 genotype of bone marrow-derived cells did not influence direct effects of Ang II on vascular function. These data provide new mechanistic insight into the influence of SOCS3 on the vasculature, including divergent effects depending on the source of Ang II. Bone marrow-derived cells deficient in SOCS3 protect against systemic Ang II-induced vascular dysfunction.

scholarly journals Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Aburrahman Gun ◽  
Mehmet Kaya Ozer ◽  
Sedat Bilgic ◽  
Nevin Kocaman ◽  
Gonca Ozan
Keyword(s):  
Metabolic Syndrome ◽  
Caffeic Acid ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Caffeic Acid Phenethyl Ester ◽  
High Fructose Corn Syrup ◽  
Corn Syrup ◽  
Beneficial Effects ◽  
Fructose Intake ◽  
High Fructose

Fructose corn syrup is cheap sweetener and prolongs the shelf life of products, but fructose intake causes hyperinsulinemia, hypertriglyceridemia, and hypertension. All of them are referred to as metabolic syndrome and they are risk factors for cardiovascular diseases. Hence, the harmful effects of increased fructose intake on health and their prevention should take greater consideration. Caffeic Acid Phenethyl Ester (CAPE) has beneficial effects on metabolic syndrome and vascular function which is important in the prevention of cardiovascular disease. However, there are no known studies about the effect of CAPE on fructose-induced vascular dysfunction. In this study, we examined the effect of CAPE on vascular dysfunction due to high fructose corn syrup (HFCS). HFCS (6 weeks, 30% fed with drinking water) caused vascular dysfunction, but treatment with CAPE (50 micromol/kg i.p. for the last two weeks) effectively restored this problem. Additionally, hypertension in HFCS-fed rats was also decreased in CAPE supplemented rats. CAPE supplements lowered HFCS consumption-induced raise in blood glucose, homocysteine, and cholesterol levels. The aorta tissue endothelial nitric oxide synthase (eNOS) production was decreased in rats given HFCS and in contrast CAPE supplementation efficiently increased its production. The presented results showed that HFCS-induced cardiovascular abnormalities could be prevented by CAPE treatment.

scholarly journals Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

2018 ◽  
Vol 314 (5) ◽  
pp. E468-E477 ◽  
Author(s):  
Micah L. Battson ◽  
Dustin M. Lee ◽  
Dillon K. Jarrell ◽  
Shuofei Hou ◽  
Kayl E. Ecton ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Nuclear Factor Κb ◽  
Western Diet ◽  
Standard Diet ◽  
Vascular Abnormalities ◽  
Gut Dysbiosis

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) ( n = 12) or Western diet (WD) ( n = 24) for 5 mo, after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) ( n = 12/group) for 2 mo. Seven months of WD caused gut dysbiosis, increased arterial stiffness (SD 412.0 ± 6.0 vs. WD 458.3 ± 9.0 cm/s, P < 0.05) and endothelial dysfunction (28% decrease in max dilation, P < 0.05), and reduced l-NAME-inhibited dilation. Vascular dysfunction was accompanied by significant increases in circulating LPS-binding protein (LBP) (SD 5.26 ± 0.23 vs. WD 11 ± 0.86 µg/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 ± 0.25 vs. WD 7.09 ± 1.07 pg/ml, P < 0.05); aortic expression of phosphorylated nuclear factor-κB (p-NF-κB) ( P < 0.05); and perivascular adipose expression of NADPH oxidase subunit p67phox ( P < 0.05). Impairments in vascular function correlated with reductions in Bifidobacterium spp. Antibiotic treatment successfully abrogated the gut microbiota and reversed WD-induced arterial stiffness and endothelial dysfunction. These improvements were accompanied by significant reductions in LBP, IL-6, p-NF-κB, and advanced glycation end products (AGEs), and were independent from changes in body weight and glucose tolerance. These results indicate that gut dysbiosis contributes to the development of WD-induced vascular dysfunction, and identify the gut microbiota as a novel therapeutic target for obesity-related vascular abnormalities.

Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

2005 ◽  
Vol 289 (1) ◽  
pp. H206-H211 ◽  
Author(s):  
Hong Ding ◽  
Andrew G. Howarth ◽  
Malarvannan Pannirselvam ◽  
Todd J. Anderson ◽  
David L. Severson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Mesenteric Arteries ◽  
Mrna Levels ◽  
Important Indicator ◽  
Membrane Function

The Type 2 diabetic db/ db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMAs). Contractions of SMAs from the db/ db mouse to the α1-adrenoceptor agonist phenylephrine (PE) were significantly enhanced, and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/ db mice with a nonthiazolidinedione peroxisome prolifetor-activated receptor-γ agonist and insulin sensitizing agent 2-[2-(4-phenoxy-2-propylphenoxy)ethyl]indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with the discontinuation of therapy, endothelial dysfunction returned. Dysfunctional SMAs were found to specifically upregulate the expression of a 35-kDa isoform of sarcolemmal membrane-associated protein (SLMAP), which is a component of the excitation-contraction coupling apparatus and implicated in the regulation of membrane function in muscle cells. Real-time PCR revealed high SLMAP mRNA levels in the db/ db microvasculature, which were markedly downregulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/ db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the overexpression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with Type 2 diabetes.

scholarly journals Exploring the Association between Vascular Dysfunction and Skeletal Muscle Mass, Strength and Function in Healthy Adults: A Systematic Review

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 715 ◽  
Author(s):  
Svyatoslav Dvoretskiy ◽  
Jacqueline C. Lieblein-Boff ◽  
Satya Jonnalagadda ◽  
Philip J. Atherton ◽  
Bethan E. Phillips ◽  
...  
Keyword(s):  
Systematic Review ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Healthy Adults ◽  
Exercise Interventions ◽  
Randomized Controlled Studies ◽  
Muscle Health ◽  
And Function

Background: The prevalence of vascular dysfunction increases with advancing age, as does the loss of muscle mass, strength and function. This systematic review explores the association between vascular dysfunction and skeletal muscle health in healthy adults. Methods: EMBASE and MEDLINE were searched for cross-sectional and randomized controlled studies between January 2009 and April 2019, with 33 out of 1246 studies included based on predefined criteria. Assessments of muscular health included muscle mass, strength and function. Macrovascular function assessment included arterial stiffness (pulse wave velocity or augmentation index), carotid intima-media thickness, and flow-mediated dilation. Microvascular health assessment included capillary density or microvascular flow (contrast enhanced ultrasound). Results: All 33 studies demonstrated a significant association between vascular function and skeletal muscle health. Significant negative associations were reported between vascular dysfunction and -muscle strength (10 studies); -mass (9 studies); and -function (5 studies). Nine studies reported positive correlations between muscle mass and microvascular health. Conclusions: Multiple studies have revealed an association between vascular status and skeletal muscle health in healthy adults. This review points to the importance of screening for muscle health in adults with vascular dysfunction with a view to initiating early nutrition and exercise interventions to ameliorate functional decline over time.

scholarly journals Vascular senescence and ageing: a role for the MEOX proteins in promoting endothelial dysfunction

2017 ◽  
Vol 95 (10) ◽  
pp. 1067-1077 ◽  
Author(s):  
Josette M. Northcott ◽  
Michael P. Czubryt ◽  
Jeffrey T. Wigle
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Disease ◽  
Vascular Function ◽  
Vascular System ◽  
Vascular Dysfunction ◽  
Enos Expression ◽  
Angiogenic Potential ◽  
Protein Levels ◽  
Increased Risk

In the vascular system, ageing is accompanied by the accrual of senescent cells and is associated with an increased risk of vascular disease. Endothelial cell (EC) dysfunction is a hallmark of vascular disease and is characterized by decreased angiogenic potential, reduced nitric oxide bioavailability, impaired vasodilation, increased production of ROS, and enhanced inflammation. In ECs, the major producer of nitric oxide is the endothelial nitric oxide synthase (eNOS) enzyme that is encoded by the NOS3 gene. NOS3/eNOS function is tightly regulated at both the transcriptional and post-transcriptional levels to maintain normal vascular function. A key transcriptional regulator of eNOS expression is p53, which has been shown to play a central role in mediating cellular senescence and thereby vascular dysfunction. Herein, we show that, in ECs, the MEOX homeodomain transcription factors decrease the expression of genes involved in angiogenesis, repress eNOS expression at the mRNA and protein levels, and increase the expression of p53. These findings support a role for the MEOX proteins in promoting endothelial dysfunction.

Abstract 099: Fetuin-A and Toll-like Receptor 4 Regulate Vascular Function: Role of Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Augusto C Montezano ◽  
Karla B Neves ◽  
Rheure A Lopes ◽  
Susan Leckerman ◽  
Anastasiya Strembitska ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Protein Oxidation ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Mesenteric Arteries ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Fetuin A

Fetuin-A (FetA) regulates calcium and phosphate homeostasis. It is also an agonist to toll-like receptor 4 (TLR4) and is related to insulin resistance and inflammation. FetA has also been associated with endothelial dysfunction, which is regulated by oxidative stress. Mechanisms whereby FetA influences vascular function are unknown. We hypothesized that FetA through TLR4 and ROS production induces vascular dysfunction. Mesenteric arteries and vascular cells from WKY rats were studied. Vascular function was analysed by wire myography in the presence or absence of FetA (50 ng/mL) and/or CLI095 (CLI - 10-6M - TLR4 inhibitor). Levels of reactive oxygen species (ROS) were measured by chemiluminescence, Amplex Red (H2O2) and ELISA (nitrotyrosine) Protein oxidation and levels were measured by immunoblotting. WKY vessels exposed to FetA were less sensitive to acetylcholine (Ach)-induced and sodium nitroprusside (SNP)-induced relaxation, while sensitivity to phenylephrine was increased by FetA; an effect blocked by N-acetylcysteine (antioxidant) and ML171 (Nox1 inhibitor). Inhibition of TLR4 blocked FetA effects on endothelial-dependent relaxation and contraction, but not on endothelial-independent relaxation. FetA increased ROS production (131±49.2%), but decreased H2O2 intracellular levels (63±14%) in endothelial cells (EC) (vs. veh, p<0.05); an effect blocked by CLI095. ROS production (66±12.2%), as well as, H2O2 (45±8%) and ONOO- (105±31.6%) levels, were increased by FetA in VSMCs (vs. veh, p<0.05). Protein oxidation was increased by FetA in VSMCs (103±26% vs. veh, p<0.05). In EC, eNOS inactivation (136±38%) and JNK activation (84±5%) were increased by FetA (vs. veh, p<0.05). In VSMCs, Rho kinase activity was increased (200±25% vs. veh, p<0.05) at 30 min; while myosin light chain (MLC) activation was only increased (25±3.56% vs. veh, p<0.05) at 15 min. In summary, FetA influences vascular function through Nox1-ROS dependent mechanisms. FetA-induced endothelial dysfunction and contractile responses involve TLR4. Our findings identify a novel system whereby FetA differentially influences vascular function through Nox1-ROS and TLR4. Vascular responses to FetA may depend on the specific pathway activated.

scholarly journals Peripheral Vascular Dysfunction in Chronic Kidney Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Christopher R. Martens ◽  
David G. Edwards
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Peripheral Vascular ◽  
Peripheral Vasculature ◽  
Culture Studies ◽  
Arginine Deficiency ◽  
Related Mortality

There is an increased prevalence of cardiovascular disease- (CVD-) related mortality in patients with chronic kidney disease (CKD). Endothelial dysfunction is a primary event in the development of atherosclerosis and hypertension and likely contributes to the elevated cardiovascular risk in CKD. Endothelial dysfunction has been shown to occur in the peripheral vasculature of patients with both severe and moderate CKD. Mechanisms include oxidative stress, L-arginine deficiency, and elevated plasma levels of ADMA. Interventions designed to restore vascular function in patients with CKD have shown mixed results. Evidence from cell culture studies suggest that the accumulation of uremic toxins inhibits L-arginine transport and reduces nitric oxide production. The results of these studies suggest that endothelial dysfunction may become less reversible with advancing kidney disease. The purpose of this paper is to present the current literature pertaining to potential mechanisms of peripheral vascular dysfunction in chronic kidney disease and to identify possible targets for treatment.

scholarly journals High Soluble Endoglin Levels Affect Aortic Vascular Function during Mice Aging

2021 ◽  
Vol 8 (12) ◽  
pp. 173
Author(s):  
Iveta Nejmanová ◽  
Barbora Vitverová ◽  
Samira Eissazadeh ◽  
Katarina Tripská ◽  
Ivone Cristina Igreja Sa ◽  
...  
Keyword(s):  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Type Ii Diabetes Mellitus ◽  
Pharmacological Intervention ◽  
Control Group ◽  
Chow Diet ◽  
Soluble Endoglin ◽  
Atherosclerosis Development

Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different endoglin forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. Moreover, sEng was shown to aggravate endothelial dysfunction when combined with a high-fat diet, suggesting it might be a risk factor for the development of endothelial dysfunction in combination with other risk factors. Therefore, this study hypothesized that high sEng levels exposure for 12 months combined with aging (an essential risk factor of atherosclerosis development) would aggravate vascular function in mouse aorta. Male transgenic mice with high levels of human sEng in plasma (Sol-Eng+) and their age-matched male transgenic littermates that do not develop high soluble endoglin (Control) on a chow diet were used. The aging process was initiated to contribute to endothelial dysfunction/atherosclerosis development, and it lasted 12 months. Wire myograph analysis showed impairment contractility in the Sol-Eng+ group when compared to the control group after KCl and PGF2α administration. Endothelium-dependent responsiveness to Ach was not significantly different between these groups. Western blot analysis revealed significantly decreased protein expression of Eng, p-eNOS, and ID1 expression in the Sol-Eng+ group compared to the control group suggesting reduced Eng signaling. In conclusion, we demonstrated for the first time that long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. These findings suggest that sEng can be considered a risk factor for the development of vascular dysfunction during aging and a potential therapeutical target for pharmacological intervention.

Mitochondrial Contributions to Vascular Endothelial Dysfunction, Arterial Stiffness and Cardiovascular Diseases

2021 ◽  
Author(s):  
Danielle L. Kirkman ◽  
Austin T. Robinson ◽  
Matthew J. Rossman ◽  
Douglas R. Seals ◽  
David G. Edwards
Keyword(s):  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Current Evidence ◽  
Vascular Endothelial ◽  
Cvd Risk ◽  
Important Player ◽  
Related Mortality

Cardiovascular diseases (CVD) affect 1 in 3 adults and remain the leading causes of death in America. Advancing age is the major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age and disease related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondria derived reactive oxygen species, impaired mitochondrial quality control and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.

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