Age-associated impairment in TNF-α cardioprotection from myocardial infarction

2003 ◽  
Vol 285 (2) ◽  
pp. H463-H469 ◽  
Author(s):  
Dongqing Cai ◽  
Munira Xaymardan ◽  
Jacquelyne M. Holm ◽  
Jingang Zheng ◽  
Jorge R. Kizer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Left Ventricular ◽  
Microvascular Endothelial Cells ◽  
Older Individuals ◽  
Aging Heart ◽  
Functional Studies ◽  
Tnf Α ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells

Age-associated dysfunction in cardiac microvascular endothelial cells with impaired induction of cardioprotective platelet-derived growth factor (PDGF)-dependent pathways suggests that alterations in critical vascular receptor(s) may contribute to the increased severity of cardiovascular pathology in older persons. In vivo murine phage-display peptide library biopanning revealed a senescent decrease in cardiac microvascular binding of phage epitopes homologous to tumor necrosis factor-α (TNF-α), suggesting that its receptor(s) may be downregulated in older cardiac endothelial cells. Immunostaining demonstrated that TNF-receptor 1 (TNF-R1) density was significantly lower in the subendocardial endothelium of the aging murine heart. Functional studies confirmed the senescent dysregulation of TNF-α receptor pathways, demonstrating that TNF-α induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF-α mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF-α significantly reduced the extent of myocardial injury after coronary ligation: TNF-α, 7.9 ± 1.9% left ventricular injury ( n = 4) versus PBS, 16.2 ± 7.9% ( n = 10; P < 0.05). The addition of PDGF-AB did not augment the cardioprotective action of TNF-α. In myocardial infarctions of older hearts, however, TNF-α induced significant postcoronary occlusion mortality (TNF-α 80% vs. PBS 0%; n = 10 each, P < 0.05) that was reversed by the coadministration of PDGF-AB. Overall, these studies demonstrate that aging-associated alterations in TNF-α receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF-α receptor-mediated expression of PDGF-B may improve cardiac microvascular function and provide novel approaches for treatment and possible prevention of cardiovascular disease in older individuals.

scholarly journals Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects

2012 ◽  
Vol 215 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Karolina Bäck ◽  
Rakibul Islam ◽  
Git S Johansson ◽  
Simona I Chisalita ◽  
Hans J Arnqvist
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Microvascular Endothelial Cells ◽  
Tnf Α ◽  
Glucose Accumulation ◽  
Anti Inflammatory ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells

Diabetes is associated with microcirculatory dysfunction and heart failure and changes in insulin and IGF1 levels. Whether human cardiac microvascular endothelial cells (HMVEC-Cs) are sensitive to insulin and/or IGF1 is not known. We studied the role of insulin receptors (IRs) and IGF1 receptors (IGF1Rs) in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF1 in HMVEC-Cs and human umbilical vein endothelial cells (HUVECs). IR and IGF1R gene expression was studied using real-time RT-PCR. Receptor protein expression and phosphorylation were determined by western blot and ELISA. Metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate inflammatory responses. According to gene expression and protein in HMVEC-Cs and HUVECs, IGF1R is more abundant than IR. Immunoprecipitation with anti-IGF1R antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF1 hybrid receptors in HMVEC-Cs. IGF1 at a concentration of 10−8 mol/l significantly stimulated phosphorylation of both IGF1R and IR in HMVEC-Cs. In HUVECs IGF1 10−8 mol/l phosphorylated IGF1R. IGF1 stimulated DNA synthesis at 10−8 mol/l and glucose accumulation at 10−7 mol/l in HMVEC-Cs. TNF-α dramatically increased E-selectin expression, but no inflammatory or anti-inflammatory effects of insulin, IGF1 or high glucose were seen. We conclude that HMVEC-Cs express more IGF1Rs than IRs, and mainly react to IGF1 due to the predominance of IGF1Rs and insulin/IGF1 hybrid receptors. TNF-α has a pronounced pro-inflammatory effect in HMVEC-Cs, which is not counteracted by insulin or IGF1.

Interleukin-1β increases expression and activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: role of PKCα/β1and MAPKs

2007 ◽  
Vol 292 (2) ◽  
pp. C867-C875 ◽  
Author(s):  
Deidra J. H. Mountain ◽  
Mahipal Singh ◽  
Bindu Menon ◽  
Krishna Singh
Keyword(s):  
Endothelial Cells ◽  
Cdna Array ◽  
Left Ventricular ◽  
Interleukin 1Β ◽  
Matrix Metalloproteinase 2 ◽  
Microvascular Endothelial Cells ◽  
Protein Levels ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells ◽  
Expression And Activity

Matrix metalloproteinases (MMPs), a family of extracellular endopeptidases, are implicated in angiogenesis because of their ability to selectively degrade components of the extracellular matrix. Interleukin-1β (IL-1β), increased in the heart post-myocardial infarction (post-MI), plays a protective role in the pathophysiology of left ventricular (LV) remodeling following MI. Here we studied expression of various angiogenic genes affected by IL-1β in cardiac microvascular endothelial cells (CMECs) and investigated the signaling pathways involved in the regulation of MMP-2. cDNA array analysis of 96 angiogenesis-related genes indicated that IL-1β modulates the expression of numerous genes, notably increasing the expression of MMP-2, not MMP-9. RT-PCR and Western blot analyses confirmed increased expression of MMP-2 in response to IL-1β. Gelatin in-gel zymography and Biotrak activity assay demonstrated that IL-1β increases MMP-2 activity in the conditioned media. IL-1β activated ERK1/2, JNKs, and protein kinase C (PKC), specifically PKCα/β1, and inhibition of these cascades partially inhibited IL-1β-stimulated increases in MMP-2. Inhibition of PKCα/β1failed to inhibit ERK1/2. However, concurrent inhibition of PKCα/β1and ERK1/2 almost completely inhibited IL-1β-mediated increases in MMP-2 expression. Inhibition of p38 kinase and nuclear factor-κB (NF-κB) had no effect. Pretreatment with superoxide dismutase (SOD) mimetic, MnTMPyP, increased MMP-2 protein levels, whereas pretreatment with SOD and catalase mimetic, EUK134, partially inhibited IL-1β-stimulated increases in MMP-2 protein levels. Exogenous H2O2significantly increased MMP-2 protein levels, whereas superoxide generation by xanthine/xanthine oxidase had no effect. This in vitro study suggests that IL-1β modulates expression and activity of MMP-2 in CMECs.

Abstract 278: Targeted Anticancer Drug Sorafenib Impairs Vascular Network Formation by Human Cardiac Microvascular Endothelial Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Eugene Konorev ◽  
Zuyue Sun ◽  
Frederick Taylor ◽  
Jay Malmo
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Microvascular Endothelial Cells ◽  
Vascular Networks ◽  
Vitro Assay ◽  
Vascular Growth ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells

Sorafenib is a novel multikinase inhibitor drug that is approved for the treatment of renal cell carcinoma and hepatocellular carcinoma, and is being tested in other common types of cancers. Recent clinical trials revealed that the use of this agent is associated with such cardiovascular complications as hypertension and reduced left ventricular ejection fraction. Sorafenib is known to inhibit Raf kinase, as well as VEGFR2 and PDGF receptor tyrosine kinase activities. We set out to test the hypothesis that sorafenib suppresses cardiac endothelial functions and angiogenesis. We treated human cardiac microvascular endothelial cells (HCMVEC) with VEGF, FGF2, and PDGF-BB in order to examine effects of sorafenib on signaling pathways activated by these pro-angiogenic factors. We determined in these studies that VEGFR2 tyrosine kinase was the most sensitive target of sorafenib in human cardiac endothelial cells. As a result, sorafenib inhibited proliferation and viability of HCMVEC. In order to examine effects of sorafenib on cardiac angiogenesis, we used a co-culture assay of HCMVEC with human cardiac fibroblasts. Sorafenib suppressed the formation of vascular networks in this in vitro assay with an IC50 of approximately 30 nM. In an in vivo Matrigel plug assay, VEGF and FGF2 were admixed into Matrigel before injecting it to mice in order to induce vascular growth within the plug. Control plugs exhibited robust development of vascular networks while sorafenib (daily injections of 30 mg/kg) severely inhibited vascular growth within the plugs. Taken together, this data provide the evidence that endothelial cells present a viable target of sorafenib in the heart.

scholarly journals Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

2021 ◽  
Vol 118 (8) ◽  
pp. e2016950118 ◽  
Author(s):  
Tyler M. Lu ◽  
Sean Houghton ◽  
Tarig Magdeldin ◽  
José Gabriel Barcia Durán ◽  
Andrew P. Minotti ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neurological Diseases ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Microvascular Endothelium ◽  
Functional Studies ◽  
Bona Fide ◽  
Microvascular Endothelial

Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood–brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (ETV2, ERG, and FLI1) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery.

Resveratrol Reduces Matrix Metalloproteinase-2 Activity Induced by Oxygen-Glucose Deprivation and Reoxygenation in Human Cerebral Microvascular Endothelial Cells

2012 ◽  
Vol 82 (4) ◽  
pp. 267-274 ◽  
Author(s):  
Zahide Cavdar ◽  
Mehtap Y. Egrilmez ◽  
Zekiye S. Altun ◽  
Nur Arslan ◽  
Nilgun Yener ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neurovascular Unit ◽  
Glucose Deprivation ◽  
Matrix Metalloproteinase 2 ◽  
Microvascular Endothelial Cells ◽  
Oxygen Glucose Deprivation ◽  
Microvascular Endothelial

The main pathophysiology in cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Among the human matrix metalloproteinases (MMPs), MMP-2 and -9, known as gelatinases, are the key enzymes for degrading type IV collagen, which is the major component of the basal membrane that surrounds the cerebral blood vessel. In the present study, we investigated the effects of resveratrol on cytotoxicity, reactive oxygen species (ROS), and gelatinases (MMP-2 and -9) in human cerebral microvascular endothelial cells exposed to 6 hours of oxygen-glucose deprivation and a subsequent 24 hours of reoxygenation with glucose (OGD/R), to mimic ischemia/reperfusion in vivo. Lactate dehydrogenase increased significantly, in comparison to that in the normoxia group. ROS was markedly increased in the OGD/R group, compared to normoxia. Correspondingly, ROS was significantly reduced with 50 μM of resveratrol. The proMMP-2 activity in the OGD/R group showed a statistically significant increase from the control cells. Resveratrol preconditioning decreased significantly the proMMP-2 in the cells exposed to OGD/R in comparison to that in the OGD/R group. Our results indicate that resveratrol regulates MMP-2 activity induced by OGD/R via its antioxidant effect, implying a possible mechanism related to the neuroprotective effect of resveratrol.

scholarly journals Anti-Inflammatory Effect and Cellular Uptake Mechanism of Carbon Nanodots in in Human Microvascular Endothelial Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1247
Author(s):  
Sarah Belperain ◽  
Zi Yae Kang ◽  
Andrew Dunphy ◽  
Brandon Priebe ◽  
Norman H. L. Chiu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
Antioxidant Properties ◽  
Synthesis Method ◽  
Microvascular Endothelial Cells ◽  
Carbon Nanodots ◽  
Uptake Mechanism ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Microvascular Endothelial

Cardiovascular disease (CVD) has become an increasingly important topic in the field of medical research due to the steadily increasing rates of mortality caused by this disease. With recent advancements in nanotechnology, a push for new, novel treatments for CVD utilizing these new materials has begun. Carbon Nanodots (CNDs), are a new form of nanoparticles that have been coveted due to the green synthesis method, biocompatibility, fluorescent capabilities and potential anti-antioxidant properties. With much research pouring into CNDs being used as bioimaging and drug delivery tools, few studies have been completed on their anti-inflammatory potential, especially in the cardiovascular system. CVD begins initially by endothelial cell inflammation. The cause of this inflammation can come from many sources; one being tumor necrosis factor (TNF-α), which can not only trigger inflammation but prolong its existence by causing a storm of pro-inflammatory cytokines. This study investigated the ability of CNDs to attenuate TNF-α induced inflammation in human microvascular endothelial cells (HMEC-1). Results show that CNDs at non-cytotoxic concentrations reduce the expression of pro-inflammatory genes, mainly Interleukin-8 (IL-8), and interleukin 1 beta (IL-1β). The uptake of CNDs by HMEC-1s was examined. Results from the studies involving channel blockers and endocytosis disruptors suggest that uptake takes place by endocytosis. These findings provide insights on the interaction CNDs and endothelial cells undergoing TNF-α induced cellular inflammation.

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