Undercarboxylated osteocalcin has no adverse effect on endothelial function in rabbit aorta or human vascular cells

Introduction: Resolvin-D1 (RvD1) and other specialized pro-resolving lipid mediators (SPM) are synthesized in-vivo from docosahexaenoic acid (DHA) through transcellular pathways involving leukocytes. We investigated if vascular tissues, in the absence of inflammatory cells, can contribute to the local production of SPM. Methods: Primary cultures of human saphenous vein endothelial (EC) and smooth muscle (SMC) cells were supplemented with DHA in cell culture media (10% serum) for 4h-24h. Freshly harvested rabbit aorta was incubated intact or following gentle EC denudation in medium with or without DHA for 48h. RvD1 levels were quantified by ELISA, and lipoxygenase (LO) expression by western blotting. Results: In the absence of DHA supplementation, EC and SMC produced undetectable levels of RvD1. DHA treatment produced a dose and time-dependent increase in RvD1 production by EC and SMC (10.1 ±1.0 pg, 7.4 ±0.2 pg respectively; 1000nM DHA; 24h; Fig A, B). 5-LO expression was demonstrated in both cell types, however DHA induced increased 5-LO expression in EC (Fig C) but not in SMC. DHA-treated intact rabbit aorta segments produced 0.24±0.05 pg RvD1/mg tissue versus 0.13±0.01 pg RvD1/mg tissue in media alone. Moreover, EC-denuded aortas produced significantly less RvD1 (Fig D). Conclusions: Human vascular cells and rabbit vascular tissue can biosynthesize RvD1 de novo from its precursor DHA, signifying a potentially important local source of SPM in the vasculature.

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Undercarboxylated osteocalcin is associated with vascular function in female older adults but does not influence vascular function in male rabbit carotid artery ex vivo

PLoS ONE ◽

10.1371/journal.pone.0242774 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0242774

Author(s):

Alexander Tacey ◽

Cassandra Smith ◽

Mary N. Woessner ◽

Paul Chubb ◽

Christopher Neil ◽

...

Keyword(s):

Blood Pressure ◽

Older Adults ◽

Carotid Artery ◽

Endothelial Function ◽

Vascular Function ◽

Ex Vivo ◽

Atherogenic Diet ◽

Undercarboxylated Osteocalcin ◽

Menopausal Women ◽

Post Menopausal

Background There are conflicting reports on the association of undercarboxylated osteocalcin (ucOC) in cardiovascular disease development, including endothelial function and hypertension. We tested whether ucOC is related to blood pressure and endothelial function in older adults, and if ucOC directly affects endothelial-mediated vasodilation in the carotid artery of rabbits. Methods In older adults, ucOC, blood pressure, pulse wave velocity (PWV) and brachial artery flow-mediated dilation (BAFMD) were measured (n = 38, 26 post-menopausal women and 12 men, mean age 73 ± 0.96). The vasoactivity of the carotid artery was assessed in male New Zealand White rabbits following a four-week normal or atherogenic diet using perfusion myography. An ucOC dose response curve (0.3–45 ng/ml) was generated following incubation of the arteries for 2-hours in either normal or high glucose conditions. Results ucOC levels were higher in normotensive older adults compared to those with stage 2 hypertension (p < 0.05), particularly in women (p < 0.01). In all participants, higher ucOC was associated with lower PWV (p < 0.05), but not BAFMD (p > 0.05). In rabbits, ucOC at any dose did not alter vasoactivity of the carotid artery, either following a normal or an atherogenic diet (p > 0.05). Conclusion Increased ucOC is associated with lower blood pressure and increased arterial stiffness, particularly in post-menopausal women. However, ucOC administration has no direct short-term effect on endothelial function in rabbit arteries. Future studies should explore whether treatment with ucOC, in vivo, has direct or indirect effects on blood vessel function.

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Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease

Nutrients ◽

10.3390/nu10101426 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1426 ◽

Cited By ~ 15

Author(s):

Alexander Tacey ◽

Tawar Qaradakhi ◽

Tara Brennan-Speranza ◽

Alan Hayes ◽

Anthony Zulli ◽

...

Keyword(s):

Vascular Calcification ◽

Undercarboxylated Osteocalcin ◽

Vascular Cells ◽

Metabolic Factors ◽

Atherosclerotic Vascular Disease ◽

Glucose And Lipid Metabolism ◽

Metabolic Functions ◽

Atherosclerosis Development ◽

Phosphoinositide 3 Kinase

There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. Osteocalcin, an osteoblast derived protein, exists in two forms, carboxylated and undercarboxylated osteocalcin. Undercarboxylated osteocalcin has been linked to the regulation of metabolic functions, including glucose and lipid metabolism. Features of atherosclerosis have been associated with circulating osteocalcin; however, this association is often conflicting and unclear. Therefore, the aim of this review is to examine the evidence for a role of osteocalcin in atherosclerosis development and progression, and in particular endothelial dysfunction and vascular calcification. The current literature suggests that undercarboxylated osteocalcin stimulates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to upregulate nitric oxide and nuclear factor kappa β (NF-кβ) in vascular cells, possibly protecting endothelial function and preventing atherogenesis. However, this effect may be mediated by metabolic factors, such as improvements in insulin signaling, rather than through a direct effect on the vasculature. Total osteocalcin is frequently associated with vascular calcification, an association that may occur as a result of vascular cells eliciting an osteogenic phenotype. Whether osteocalcin acts as a mediator or a marker of vascular calcification is currently unclear. As such, further studies that examine each form of osteocalcin are required to elucidate if it is a mediator of atherogenesis, and whether it functions independently of metabolic factors.

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Lysosomal hydrolases of human vascular cells: response to agonists of endothelial function

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/0167-4889(89)90159-6 ◽

1989 ◽

Vol 1010 (2) ◽

pp. 184-190 ◽

Cited By ~ 2

Author(s):

David M.L. Morgan ◽

Jeremy D. Pearson ◽

John L. Gordon

Keyword(s):

Endothelial Function ◽

Vascular Cells ◽

Lysosomal Hydrolases

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Acetylsalicylate reduces endothelial and platelet-derived microparticles in patients with coronary artery disease

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y11-013 ◽

2011 ◽

Vol 89 (4) ◽

pp. 239-244 ◽

Cited By ~ 39

Author(s):

Daniel Bulut ◽

Vanessa Becker ◽

Andreas Mügge

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Endothelial Function ◽

Preventive Therapy ◽

Vascular Cells ◽

Circulating Microparticles ◽

Cox 2 ◽

Artery Disease ◽

Flow Mediated Vasodilation ◽

The Impact

Previous studies suggest that endothelial progenitor cells (EPCs) contribute to vascular repair processes. In contrast, circulating microparticles (MPs) are reported to be part of a process that is damaging to vascular cells. Numerous studies suggest that the “balance” between EPCs and MPs is important for the integrity of vascular cells and preservation of endothelial function. In the present study, we assess the impact of acetylsalicylate (ASA) — which is, beside statins and physical exercise, a third basic column in the preventive therapy of coronary artery disease (CAD) — on EPCs and MPs in patients with CAD. We investigated the effect of treatment (8 weeks) with ASA (100 mg/d) on endothelial function (flow-mediated vasodilation, FMD), number of circulating EPCs, and endothelial- and platelet-derived microparticles (eMP, pMP) in 15 male patients (age 59.5 ± 12.3 years) with CAD but nonsignificant stenosis. The number of pMPs and eMPs decreased by 62.7% (p < 0.05) and 28.4% (p < 0.05), respectively. The number of circulating EPCs (VEGFR2+CD34+), expressed as ‰ of circulating polymorphonuclear leukocytes, remained unchanged. Despite the reduced number of pMPs and eMPs in response to the ASA therapy, the FMD responses and the maximal dilator effects of nitroglycerin were unaffected. In a control experiment, patients (n = 6) treated with the selective COX-2 inhibitor etoricoxib (90 mg/day) for 8 weeks showed no changes in the number of pMPs, eMPs, and EPCs and in FMD. We report on a novel effect of ASA treatment on the number of circulating endothelial- and platelet-derived microparticles in patients with cardiovascular disease. The mechanism remains elusive, and appears not to be associated with the COX-2 pathway.

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Sexual dimorphism in rabbit aortic endothelial function under acute hyperglycemic conditions and gender-specific responses to acute 17β-estradiol

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01217.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. H2411-H2420 ◽

Cited By ~ 9

Author(s):

Aditya Goel ◽

Der Thor ◽

Leigh Anderson ◽

Roshanak Rahimian

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Rabbit Aorta ◽

Epidemiological Data ◽

Male And Female ◽

Pkc Isoforms ◽

17Β Estradiol ◽

Pkc Β ◽

Estrogen Administration

Epidemiological data suggest that hyperglycemia abrogates the gender-based cardiovascular protection possibly associated with estrogens. This study was designed to investigate 1) whether rabbit aortic rings show gender differences in the development of abnormal endothelium-dependent vasodilation (EDV) under acute hyperglycemic conditions, 2) the potential role of PKC isoforms and superoxide (O2−) in acute hyperglycemia-induced vascular dysfunction, and 3) the effect of acute estrogen administration on hyperglycemia-induced endothelial dysfunction in male and female rabbits. EDV to ACh was determined before and after 3 h of treatment with high glucose (HG) in phenylephrine-precontracted aortic rings from male and female New Zealand White rabbits. Similar experiments were conducted in the presence of inhibitors of PKC-α, PKC-β, and PKC-δ or an O2− scavenger. The effect of acute estrogen administration was evaluated in the presence and absence of HG. Finally, mRNA expression of PKC isoforms was measured by real-time PCR. We found that 1) 3 h of incubation with HG impairs EDV to a greater extent in female than male aorta, 2) inhibition of PKC-β or O2− prevents HG-induced impairment of EDV in female aorta, 3) acute 17β-estradiol aggravates HG-induced endothelial dysfunction in female, but not male, aorta, and 4) PKC-α and PKC-β expression are significantly higher in female than male aorta. This study reveals the predisposition of female rabbit aorta to vascular injury under hyperglycemic conditions, possibly via activation of PKC-β and O2− production. Furthermore, it suggests that, under hyperglycemic conditions, acute estrogen treatment is detrimental to endothelial function in female rabbits.

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Male Subclinical Hypogonadism: Mechanisms with Interplay of Reproductive Hormones, Undercarboxylated Osteocalcin and Endothelial Dysfunction

10.21203/rs.3.rs-951391/v1 ◽

2021 ◽

Author(s):

ragaa abdelshaheed matta ◽

Hazem Mohamed Farrage ◽

Ahmed Abdelfadel Saedii ◽

Mohamed Mamdouh Abdelrahman

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Late Onset ◽

Inflammatory Marker ◽

Reproductive Hormones ◽

Sex Hormone Binding Globulin ◽

Stiffness Index ◽

Sensitivity Index ◽

Aromatase Activity ◽

Undercarboxylated Osteocalcin

Abstract BackgroundPathogenesis and endothelial function in subclinical hypogonadism (SCH) are unknown. Undercarboxylated osteocalcin (ucOC) participate in atherosclerosis and reproduction. We studied interplay of endothelial function, unOC and reproductive hormones with SCH.Methodsamong SCH, late onset hypogonadism (LOH), and healthy eugonadal male (HC) groups, we measured sex hormones and unOC, calculated luteinizing hormone/testosterone (LH/T), LH.T product and estradiol/T (E/T) as indicators of impaired leydig cell, androgen sensitivity index (ASI) & aromatase activity respectively and regulators for LH set point. We assessed flow mediated dilation of brachial artery (FMD%), carotid- intima media thickness (CIMT) and aortic stiffness index (AS) as markers of subclinical atherosclerosis.ResultsContrary to LOH, SCH had higher ASI, lower E/T ratio& similar T, follicle stimulating hormone and sex hormone binding globulin (SHBG) compared to HC, LH/ T was significant higher in LOH and lower in HC than SCH . Similar to LOH, SCH had significant lower FMD% and higher CIMT, AS, unOC & inflammatory marker and atherogenic lipid profile than HC. LH, LH/T & ucOC negatively while T positively FMD% meanwhile. LH, LH/T & ucOC positively while testosterone negatively correlated with CIMT. LH and LH/T positively while estradiol and E/T negatively related to AS. ucOC positively correlated to LH, LH/T, E SHBG & negatively correlated with T. Independent predictors were LH for FMD% & AS meanwhile LH and LH/T for CIMT.ConclusionsSCH as not impaired testicular function state is characterized by androgen insensitivity, impaired aromatase activity, compensatory elevated unOC and atherogenic role of LH in endothelial dysfunction.

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