Inflammatory markers, endothelial function and cardiovascular risk

The need to study cardiovascular diseases (CVD) has become more and more relevant as their prevalence has increased over the years. An intact endothelial wall is essential to vascular health. Certain factors are responsible for maintaining this tissue intact, including nitric oxide (NO), which provokes dilation of blood vessels in response to shear stress. Expression of the endothelial nitric oxide synthase (eNOS) enzyme, which produces nitric oxide in response to increases in blood flow, is of fundamental importance to maintenance of the vascular system. When this enzyme is inhibited, nitric oxide production is reduced, causing endothelial dysfunction. Since C-reactive protein inhibits production of nitric oxide by the eNOS enzyme, it is one of the causes of endothelial dysfunction and cardiovascular events. The objective of the present study was to review scientific articles in the literature related to the subject 'inflammatory markers and endothelial function'. A wide-ranging review of the current literature was conducted, using systematic analysis of bibliographic references indexed in PubMed, Scielo, Medline and LILACS database, for the years 1992 to 2013. The studies reviewed show that increases in inflammation causes reductions in NO and increases in cardiovascular events. Increased inflammation is associated with higher incidence of cardiovascular diseases.

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Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00540.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. E481-E495 ◽

Cited By ~ 125

Author(s):

Rinrada Kietadisorn ◽

Rio P. Juni ◽

An L. Moens

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Therapeutic Interventions ◽

Enos Uncoupling ◽

Underlying Causes ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.

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Abstract P345: Overexpression of Mitochondrial Deacetylase Sirt3 Protects Endothelial Function and Attenuates Hypertension While Sirt3 Depletion Increases Oxidative Stress and Endothelial Dysfunction Due to SOD2 Hyperacetylation

Hypertension ◽

10.1161/hyp.70.suppl_1.p345 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Anna E Dikalova ◽

Hana A Itani ◽

Arvind K Pandey ◽

David G Harrison ◽

Sergey I Dikalov

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Knockout Mice ◽

Whole Body ◽

Wild Type ◽

Endothelial Nitric Oxide

We have recently reported SOD2 hyperacetylation and reduced Sirt3 level in human subjects with essential hypertension. We hypothesized that diminished Sirt3 expression promotes endothelial dysfunction and hypertension while Sirt3 overexpression protects endothelial function and attenuates hypertension. Indeed, hypertension was markedly increased in Sirt3 knockout (Sirt3 -/- ) in response to angiotensin II (0.7 mg/kg/day) compared with wild-type C57Bl/6J mice. Sirt3 depletion caused SOD2 inactivation due to SOD2 hyperacetylation, increased mitochondrial O 2 • and diminished endothelial nitric oxide. Angiotensin II infusion in wild-type mice was associated with Sirt3 inactivation and SOD2 hyperacetylation in aorta and kidney. To test the specific role of Sirt3 in vasculature we have generated tamoxifen-inducible endothelium specific Sirt3 knockout mice (Ec Sirt3 KO ) and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ). Deletion of Sirt3 in smooth muscle exacerbated hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increased mortality in angiotensin II infused Smc Sirt3 KO mice (30% vs 3% in wild-type) which was associated with higher rate of aortic aneurysm. Ec Sirt3 KO mice had elevated basal blood pressure by 12 mm Hg and hypertension was exacerbated in Ec Sirt3 KO mice accompanied by impaired vascular relaxation and reduced endothelial nitric oxide. Treatment of angiotensin II-infused Sirt3 -/- mice with SOD2 mimetic mitoTEMPO rescued endothelial-dependent relaxation and reduced blood pressure. We tested if Sirt3 overexpression protects endothelial function and attenuates angiotensin II-induced hypertension. These new mice were obtained by crossing the EIIa-cre with Sirt3flox mice resulting in constitutively increased Sirt3 in the whole body. Sirt3 overexpression abolished angiotensin II induced impairment of vasorelaxation and attenuated development of hypertension. Our data suggest that diminished Sirt3 activity leads to SOD2 hyperacetylation and contributes to the pathogenesis of hypertension. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

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Effect of Different Classes of Antihypertensive Drugs on Endothelial Function and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20143458 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3458 ◽

Cited By ~ 20

Author(s):

Isabella Viana Gomes Silva ◽

Roberta Carvalho de Figueiredo ◽

Danyelle Romana Alves Rios

Keyword(s):

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Antihypertensive Drugs ◽

Vascular Inflammation ◽

Functional Changes ◽

Beneficial Effects ◽

Reactive Protein ◽

Pressure Lowering ◽

Effect Of Treatment

Hypertension is characterized by structural and functional changes in blood vessels that travel with increased arterial stiffness, vascular inflammation, and endothelial dysfunction. Some antihypertensive drugs have been shown to improve endothelial function and reduce levels of inflammatory markers regardless of the effect of blood pressure lowering. Third-generation β-blockers, such as nebivolol and carvedilol, because they have additional properties, have been shown to improve endothelial function in patients with hypertension. Calcium channel antagonists, because they have antioxidant effects, may improve endothelial function and vascular inflammation.The Angiotensin Receptor Blocker (ARBs) are able to improve endothelial dysfunction and vascular inflammation in patients with hypertension and other cardiovascular diseases. Angiotensin converting enzyme (ACE) inhibitors have shown beneficial effects on endothelial function in patients with hypertension and other cardiovascular diseases, however there are few studies evaluating the effect of treatment with this class on the reduction of C-reactive protein (CRP) levels. Further studies are needed to assess whether treatment of endothelial dysfunction and vascular inflammation may improve the prognosis of patients with essential hypertension.

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Exploring the Antihypertensive and Vascular-Protective Effects of Blueberries in Middle-Aged/Older Men: Study Protocol

Current Developments in Nutrition ◽

10.1093/cdn/nzaa065_010 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1745-1745

Author(s):

Emily Woolf ◽

Allegra Vazquez ◽

Sarah Johnson

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Endothelial Function ◽

Vascular System ◽

Oxidized Ldl ◽

Reactive Hyperemia ◽

Protective Effects ◽

Freeze Dried ◽

Stage 1

Abstract Objectives Previous research has demonstrated the antihypertensive and vascular-protective effects of blueberries in postmenopausal women with elevated blood pressure (BP) or stage 1-hypertension (HTN). However, this has not been explored in men with elevated BP or HTN. The objective of the present study is to examine effects of blueberry (BB) on BP, endothelial function, and arterial stiffness in men with elevated BP or stage 1-HTN, and baseline endothelial dysfunction, as well as to investigate possible mechanisms involved with BB on vascular health. Methods In a randomized, double-blind, placebo-controlled, parallel-arm trial, men with elevated BP or stage 1-HTN (systolic BP of 120–139 mmHg, and a diastolic BP < 90 mmHg), and endothelial dysfunction (reactive hyperemia index, RHI) <1.67, but otherwise healthy, will be randomized to receive either 22 g/day of freeze-dried wild BB powder or 22 g/day of placebo powder for 12 weeks. Primary outcomes for this study are BP and RHI, which is a measure of vascular endothelial function assessed using peripheral arterial tonometry. Secondary outcomes include analysis of arterial stiffness, measured by pulse wave velocity (PWV), as well as blood biomarkers of cardiovascular and metabolic health that include blood lipids, hemoglobin A1c, oxidized LDL, nitric oxide, and adhesion molecules. Furthermore, endothelial cells will be biopsied to provide mechanistic insight on how BB consumption might affect the vascular system by utilizing quantitative immunofluorescence. Results We hypothesize that 22 g/day of BB consumption (∼1 cup) for 12 weeks will improve endothelial function, arterial stiffness, and BP in men with elevated BP and/or stage 1-HTN. We also hypothesize that these improvements will be mediated by reductions in vascular oxidative stress and inflammation, and increased nitric oxide bioavailability. Conclusions This study has potential to provide unique in vivo (functional) and ex vivo (molecular) support for the hypothesis that BB consumption may attenuate endothelial dysfunction, arterial stiffness, and high BP that occurs with aging. Funding Sources Wild Blueberry Association of North America.

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Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01112.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. H801-H809 ◽

Cited By ~ 37

Author(s):

Xiaowei Sun ◽

David D. Ku

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Right Ventricular Hypertrophy ◽

Coronary Endothelial Function ◽

Novel Approach ◽

Endothelial Nitric Oxide ◽

Coronary Endothelial Dysfunction

We recently reported that increased vascular endothelial nitric oxide production could protect against the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH) in rats ( 32 ). The present study investigated whether the pleiotropic action of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in upregulating endothelial function could also protect against the MCT-induced end-organ damages. Rosuvastatin (2 mg·kg−1·day−1 via oral gavage) or placebo was initiated 1 wk before or 1 wk after MCT (60 mg/kg ip) administration. One month after MCT, significant PAH developed in the placebo rats, which were accompanied by histological evidence of pulmonary vascular thickening and right ventricular hypertrophy. The coronary endothelial vasodilatory function, assessed with endothelial/nitric oxide-dependent responses to acetylcholine and NG-nitro-l-arginine methyl ester (l-NAME), was depressed, while the constrictory responses to known coronary constrictors was enhanced. In rats that received rosuvastatin treatment 1 wk before MCT administration, a significantly reduced PAH and RVH was observed, as well as reduced pulmonary vascular and right ventricular remodelings. Rosuvastatin 1-wk posttreatment had no effect on PAH, but inhibited RVH. Right coronary endothelial dysfunction, which was shown in placebo rats, was effectively prevented by both pre- and postrosuvastatin treatment, while this effect was more dramatic in the pretreated group. Left coronary endothelial function, which was not affected by MCT, also showed an upregulation by rosuvastatin. Taken together, our results demonstrated the pleiotropic protection of rosuvastatin against the development of PAH and RVH and confirmed our previous finding that the targeted preservation of coronary endothelial function and vasoactivity may provide a novel approach to protect against cardiac remodeling.

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Molecular Mechanism of Astragaloside IV in Improving Endothelial Dysfunction of Cardiovascular Diseases Mediated by Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/1481236 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Peipei Meng ◽

Rui Yang ◽

Fenjun Jiang ◽

Jianbo Guo ◽

Xinyu Lu ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Endothelial Nitric Oxide Synthase ◽

No Production ◽

Essential Factor ◽

Astragaloside Iv ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Endothelial dysfunction, induced by oxidative stress, is an essential factor affecting cardiovascular disease. Uncoupling of endothelial nitric oxide synthase (eNOS) leads to a decrease in nitric oxide (NO) production, an increase in reactive oxygen species (ROS) production, NO consumption, and NO synthesis. As a main active ingredient of astragalus, astragaloside IV can reduce the apoptosis of endothelial cells during oxidative stress. This review is aimed at exploring the mechanism of astragaloside IV in improving oxidative stress-mediated endothelial dysfunction relevant to cardiovascular diseases. The findings showed that the astragaloside IV can prevent or reverse the uncoupling of eNOS, increase eNOS and NO, and enhance several activating enzymes to activate the antioxidant system. In-depth validation and quantitative experiments still need to be implemented.

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A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-1294 ◽

2016 ◽

Vol 101 (7) ◽

pp. 2751-2758 ◽

Cited By ~ 10

Author(s):

Cyndya A. Shibao ◽

Jorge E. Celedonio ◽

Claudia E. Ramirez ◽

Latisha Love-Gregory ◽

Amy C. Arnold ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Controlled Trial ◽

Scavenger Receptor ◽

Response To Treatment ◽

Flow Mediated Dilation ◽

Endothelial Nitric Oxide ◽

Phosphodiesterase 5

Context: The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. Objective: To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. Design: IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). Setting: Two-center study. Participants: Obese AA women. Intervention: A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. Main outcome: IS, FMD. Results: G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], −0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, −0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, −2.6 (95% CI, −5.1 to −0.1; P = .04). Conclusions: The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

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Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22179269 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9269

Author(s):

Yoshihisa Wada ◽

Reina Umeno ◽

Hajime Nagasu ◽

Megumi Kondo ◽

Atsuyuki Tokuyama ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

The Elderly ◽

Inflammasome Activation ◽

Double Knockout ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Deficient Mice

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

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Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

Current Pharmaceutical Design ◽

10.2174/1381612826666200403172736 ◽

2020 ◽

Vol 26 (30) ◽

pp. 3633-3651 ◽

Cited By ~ 2

Author(s):

Javier Blanco-Rivero ◽

Fabiano E. Xavier

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Therapeutic Potential ◽

Treatment Strategies ◽

Phosphodiesterase Inhibitors ◽

Developed Countries ◽

Major Health Problem ◽

Pde Inhibitors ◽

Pharmaceutical Industries

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

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The Use of Coenzyme Q10 in Cardiovascular Diseases

Antioxidants ◽

10.3390/antiox10050755 ◽

2021 ◽

Vol 10 (5) ◽

pp. 755

Author(s):

Yoana Rabanal-Ruiz ◽

Emilio Llanos-González ◽

Francisco J. Alcain

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Vascular System ◽

Contractile Function ◽

Artery Bypass ◽

Bypass Graft ◽

No Bioavailability ◽

Coq10 Supplementation ◽

Endogenous Antioxidant

CoQ10 is an endogenous antioxidant produced in all cells that plays an essential role in energy metabolism and antioxidant protection. CoQ10 distribution is not uniform among different organs, and the highest concentration is observed in the heart, though its levels decrease with age. Advanced age is the major risk factor for cardiovascular disease and endothelial dysfunction triggered by oxidative stress that impairs mitochondrial bioenergetic and reduces NO bioavailability, thus affecting vasodilatation. The rationale of the use of CoQ10 in cardiovascular diseases is that the loss of contractile function due to an energy depletion status in the mitochondria and reduced levels of NO for vasodilatation has been associated with low endogenous CoQ10 levels. Clinical evidence shows that CoQ10 supplementation for prolonged periods is safe, well-tolerated and significantly increases the concentration of CoQ10 in plasma up to 3–5 µg/mL. CoQ10 supplementation reduces oxidative stress and mortality from cardiovascular causes and improves clinical outcome in patients undergoing coronary artery bypass graft surgery, prevents the accumulation of oxLDL in arteries, decreases vascular stiffness and hypertension, improves endothelial dysfunction by reducing the source of ROS in the vascular system and increases the NO levels for vasodilation.

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