scholarly journals Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

2008 ◽  
Vol 295 (6) ◽  
pp. H2399-H2408 ◽  
Author(s):  
Xinwen Wang ◽  
Hong Chai ◽  
Zehao Wang ◽  
Peter H. Lin ◽  
Qizhi Yao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Coronary Arteries ◽  
Molecular Mechanisms ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Dependent Manner ◽  
Amyloid A ◽  
Enos Mrna

The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 μg/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and IκB-α after SAA treatment. Consequently, the antioxidants seleno-l-methionine and Mn(III) tetrakis-(4-benzoic acid)porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-κB. These findings suggest that SAA may contribute to the progress of coronary artery disease.

Serum amyloid A activation of human coronary artery endothelial cells exhibits a neutrophil promoting molecular profile

2013 ◽  
Vol 90 ◽  
pp. 55-63 ◽  
Author(s):  
Katja Lakota ◽  
Katjusa Mrak-Poljsak ◽  
Borut Bozic ◽  
Matija Tomsic ◽  
Snezna Sodin-Semrl
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Molecular Profile ◽  
Human Coronary Artery ◽  
Amyloid A

scholarly journals Colocalization of Serum Amyloid A with Microtubules in Human Coronary Artery Endothelial Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Katja Lakota ◽  
Nataša Resnik ◽  
Katjuša Mrak-Poljšak ◽  
Snežna Sodin-Šemrl ◽  
Peter Veranič
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Actin Filaments ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Mrna Levels ◽  
Human Coronary Artery ◽  
Double Labeling ◽  
Amyloid A ◽  
Cytoskeletal Elements

Serum amyloid A (SAA) acts as a major acute phase protein and represents a sensitive and accurate marker of inflammation. Besides its hepatic origin, as the main source of serum SAA, this protein is also produced extrahepatically. The mRNA levels of SAA become significantly elevated following proinflammatory stimuli, as well as, are induced through their own positive feedback in human primary coronary artery endothelial cells. However, the intracellular functions of SAA are so far unknown. Colocalization of SAA with cytoskeletal filaments has previously been proposed, so we analyzed the colocalization of SAA with all three cytoskeletal elements: actin filaments, vimentin filaments, and microtubules. Immunofluorescent double-labeling analyses confirmed by PLA method revealed a strict colocalization of SAA with microtubules and a very infrequent attachment to vimentin while the distribution of actin filaments appeared clearly separated from SAA staining. Also, no significant colocalization was found between SAA and endomembranes labeled with the fluorescent lipid stain DiO6. However, SAA appears to be located also unbound in the cytosol, as well as inside the nucleus and within nanotubes extending from the cells or bridging neighboring cells. These different locations of SAA in endothelial cells strongly indicate multiple potential functions of this protein.

scholarly journals Analysis of Drug Effects on Primary Human Coronary Artery Endothelial Cells Activated by Serum Amyloid A

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
K. Lakota ◽  
D. Hrušovar ◽  
M. Ogrič ◽  
K. Mrak-Poljšak ◽  
S. Čučnik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Serum Amyloid A ◽  
Certolizumab Pegol ◽  
Drug Effects ◽  
Serum Amyloid ◽  
Human Coronary Artery ◽  
Beneficial Effects ◽  
Amyloid A ◽  
Pai 1

Background. RA patients have a higher incidence of cardiovascular diseases compared to the general population. Serum amyloid A (SAA) is an acute-phase protein, upregulated in sera of RA patients. Aim. To determine the effects of medications on SAA-stimulated human coronary artery endothelial cells (HCAEC). Methods. HCAEC were preincubated for 2 h with medications from sterile ampules (dexamethasone, methotrexate, certolizumab pegol, and etanercept), dissolved in medium (captopril) or DMSO (etoricoxib, rosiglitazone, meloxicam, fluvastatin, and diclofenac). Human recombinant apo-SAA was used to stimulate HCAEC at a final 1000 nM concentration for 24 hours. IL-6, IL-8, sVCAM-1, and PAI-1 were measured by ELISA. The number of viable cells was determined colorimetrically. Results. SAA-stimulated levels of released IL-6, IL-8, and sVCAM-1 from HCAEC were significantly attenuated by methotrexate, fluvastatin, and etoricoxib. Both certolizumab pegol and etanercept significantly decreased PAI-1 by an average of 43%. Rosiglitazone significantly inhibited sVCAM-1 by 58%. Conclusion. We observed marked influence of fluvastatin on lowering cytokine production in SAA-activated HCAEC. Methotrexate showed strong beneficial effects for lowering released Il-6, IL-8, and sVCAM-1. Interesting duality was observed for NSAIDs, with meloxicam exhibiting opposite-trend effects from diclofenac and etoricoxib. This represents unique insight into specific responsiveness of inflammatory-driven HCAEC relevant to atherosclerosis.

scholarly journals Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3205-3216 ◽  
Author(s):  
Changyi Chen ◽  
Hong Chai ◽  
Xinwen Wang ◽  
Jun Jiang ◽  
Md Saha Jamaluddin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Mrna Stability ◽  
Molecular Mechanisms ◽  
Dominant Negative Mutant ◽  
Signal Pathways ◽  
Mrna Levels ◽  
Porcine Coronary Artery ◽  
Enos Mrna

Abstract The purpose of this study was to determine the effects and mechanisms of sCD40L on endothelial dysfunction in both human coronary artery endothelial cells (HCAECs) and porcine coronary artery rings. HCAECs treated with sCD40L showed significant reductions of endothelial nitric oxide synthase (eNOS) mRNA and protein levels, eNOS mRNA stability, eNOS enzyme activity, and cellular NO levels, whereas superoxide anion (O2−) production was significantly increased. sCD40L enhanced eNOS mRNA 3′UTR binding to cytoplasmic molecules and induced a unique expression pattern of 95 microRNAs. sCD40L significantly decreased mitochondrial membrane potential, and catalase and SOD activities, whereas it increased NADPH oxidase (NOX) activity. sCD40L increased phosphorylation of MAPKs p38 and ERK1/2 as well as IκBα and enhanced NF-κB nuclear translocation. In porcine coronary arteries, sCD40L significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA levels, whereas it increased O2− levels. Antioxidant seleno-l-methionine; chemical inhibitors of p38, ERK1/2, and mitochondrial complex II; as well as dominant negative mutant forms of IκBα and NOX4 effectively blocked sCD40L-induced eNOS down-regulation in HCAECs. Thus, sCD40L reduces eNOS levels, whereas it increases oxidative stress through the unique molecular mechanisms involving eNOS mRNA stability, 3′UTR-binding molecules, microRNAs, mitochondrial function, ROS-related enzymes, p38, ERK1/2, and NF-κB signal pathways in endothelial cells.

Association Between Serum Amyloid A Proteins and Coronary Artery Disease

Circulation ◽  
1997 ◽  
Vol 96 (9) ◽  
pp. 2914-2919 ◽  
Author(s):  
Alistair I. Fyfe ◽  
L.S. Rothenberg ◽  
Frederick C. DeBeer ◽  
Rita M. Cantor ◽  
Jerome I. Rotter ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Artery Disease

Abstract 84: Serum Amyloid A Does Not Modulate the Inverse Association of HDL with Coronary Artery Calcification in Type 2 Diabetes

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Claire K Mulvey ◽  
Timothy W Churchill ◽  
Karen Terembula ◽  
Jane F Ferguson ◽  
Nehal N Mehta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Logistic Regression ◽  
Coronary Artery ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Inverse Association ◽  
Tobit Regression ◽  
Amyloid A

Introduction Although high-density lipoprotein (HDL) is inversely correlated with cardiovascular risk, HDL loses its protective role in pathologic inflammatory states like type 2 diabetes (T2DM). HDL dysfunction contributes to accelerated atherosclerosis in T2DM, but the mechanism is incompletely defined. The acute phase reactant serum amyloid A (SAA) displaces apolipoprotein A-I and may impair HDL-mediated reverse cholesterol efflux. We hypothesized that SAA alters the inverse association between HDL and coronary artery calcium (CAC) in the Penn Diabetes Heart Study, a cross-sectional study of T2DM patients free of overt cardiovascular or renal disease. Methods We measured SAA in serum samples by immunonephelometry (N=975; mean age 58 ± 9 years; 63% male, 57% Caucasian; mean BMI 33 ± 6 kg/m 2 ). HDL was measured enzymatically in lipoprotein fractions after ultracentrifugation. Agatston CAC scores were quantified from electron beam tomography at the same visit. Spearman correlation and logistic regression were used to test associations of SAA with clinical factors and metabolic syndrome. We used Tobit regression to analyze associations between CAC and HDL, both overall and stratified by 3 categories of SAA: undetectable, lower half detectable, and upper half detectable. Results Spearman correlations revealed moderate association of SAA with C-reactive protein (r=0.52) and weak associations of SAA with BMI (r=0.25) and HDL (r=0.17; all p<0.001). In logistic regression, the group with highest SAA levels had increased odds of metabolic syndrome compared to those with undetectable levels (OR 1.56, 95% CI 1.03 to 2.38, p=0.036). In adjusted Tobit regression, HDL was inversely associated with CAC (Tobit coefficient for 1-SD increase in HDL: -0.30; 95% CI -0.54 to -0.06; p=0.013). Across the categories of SAA, however, there was no difference in the association of HDL with CAC (Tobit coefficient for 1-SD increase in HDL: -0.17 [95% CI -0.49 to 0.16] for undetectable vs. -0.31 [95% CI -0.79 to 0.17] for lower half detectable vs. -0.49 [95% CI -1.01 to 0.03] for upper half detectable). Conclusions Despite the association of SAA with metabolic syndrome, these data suggest that elevated SAA may not change the inverse relationship of HDL with CAC in T2DM.

Abstract 660: Local Hemodynamic Forces and Aqueous Cigarette Smoke Extract Affect Development of Endothelial Dysfunction

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sindy Giebe ◽  
Coy Brunssen ◽  
Melanie Brux ◽  
Natalia Cockcroft ◽  
Katherine Hewitt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Laminar Flow ◽  
Tobacco Smoking ◽  
Molecular Mechanisms ◽  
Low Flow ◽  
Dependent Manner ◽  
Flow Conditions ◽  
Hemodynamic Forces ◽  
Plaque Phenotype

Endothelial dysfunction is one of the first steps in the development of atherosclerosis. This proinflammatory phenotype is associated with decreased bioavailability of nitric oxide and a corresponding expression profile in the endothelial cells. Tobacco smoking promotes development of atherosclerotic plaques and local hemodynamic forces are key stimuli in this process. Low laminar flow is involved in the development of an unstable plaque phenotype, while high laminar flow has atheroprotective role. The molecular mechanisms controlling plaque stability in response to tobacco smoking remain largely unknown so far. Therefore, we exposed human endothelial cells to cigarette smoke extract (CSEaq) under disturbed flow conditions. Primary human endothelial cells were stimulated with increasing dosages of CSEaq for 24h. Cell viability was reduced by CSEaq in a dose-dependent manner. The impact of specific flow conditions and different doses of CSEaq on the expression of atherosclerosis-related genes was investigated using a cone-and-plate viscometer. High laminar flow induced elongation of endothelial cells in the direction of flow, increased eNOS expression and NO release in a time-dependent manner. This increase was inhibited by CSEaq. Low laminar flow showed no effect on eNOS expression and NO release. The NRF2 antioxidative defense system was also induced by high laminar flow. NRF2 and NRF2 target genes HMOX1 and NQO1 were strongly activated by CSEaq. Furthermore, we monitored the expression of proinflammatory genes. CSEaq strongly induced adhesion molecule ICAM-1. Interestingly, VCAM-1 was unaffected by CSEaq. Induction of endothelial NADPH oxidase isoform 4 by CSEaq was prevented by high laminar flow. Catalase expression was not affected by flow and CSEaq, whereas CSEaq transiently increased SOD1 expression. Endothelial wound healing was improved by atheroprotective high laminar flow. Low flow did not affect wound healing. Furthermore, high laminar flow decreased adhesion of monocytes to endothelial cells, compared to low flow. We suggest novel molecular mechanisms how tobacco smoking promotes the development of endothelial dysfunction. This can contribute to the formation of an unstable atherosclerotic plaque phenotype.

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