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  • 1
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    Cellular and molecular mechanisms of statins: an update on pleiotropic effects
    Portland Press Ltd. ; 2015
    In:  Clinical Science Vol. 129, No. 2 ( 2015-07-01), p. 93-105
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 129, No. 2 ( 2015-07-01), p. 93-105
    Abstract: Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti-atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20150027
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2015
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  • 2
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    Expression and localization of tumour necrosis factor-α and its converting enzyme in human abdominal aortic aneurysm
    Portland Press Ltd. ; 2004
    In:  Clinical Science Vol. 106, No. 3 ( 2004-03-01), p. 301-306
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 106, No. 3 ( 2004-03-01), p. 301-306
    Abstract: Abdominal aortic aneurysm (AAA) is characterized by chronic aortic wall inflammation and loss of matrix components. Proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) are thought to be involved in this inflammatory process and, therefore, to play an important role in the pathogenesis of human AAA. TNF-α-converting enzyme (TACE) has recently been purified and cloned as a disintegrin and metalloproteinase that converts TNF-α precursor into its mature form. The aim of the present study was to determine whether TNF-α and TACE were expressed and localized in aortic tissues in human AAA. Infrarenal aortic tissues were obtained from AAA patients (n=19) undergoing elective aneurysm reconstruction and from autopsy cases without cardiovascular disorders as normal controls (n=5). Internal thoracic artery samples were also obtained from patients with coronary artery disease undergoing coronary artery bypass grafting to represent biopsied conduit vessels (n=5). The AAA specimens were taken from the mid-portion of the aneurysm and from the longitudinal transition zone between the non-dilated aorta and the proximal aspect of the aneurysm. TNF-α and TACE mRNA levels were determined by real-time quantitative reverse transcriptase–PCR. Expression levels of both TNF-α mRNA and TACE mRNA were significantly greater in the transition zone than in the mid-portion (both P & lt;0.05). Expression levels of both forms of mRNA were significantly higher in AAA samples than in control aortas or atherosclerotic arteries. There was a significant correlation between the expression of TNF-α mRNA with that of TACE mRNA in AAA (r=0.54, P & lt;0.005). Immunostaining was positive for both TNF-α and TACE in CD68-positive macrophages in the media and adventitia obtained from the transition zone in AAA, whereas neither TNF-α nor TACE was expressed in control vessels. In conclusion, the concomitant activation and localization of TNF-α and TACE in the media and adventitia of the transition zone in human AAA underlines the importance of this system in the pathogenesis of this disorder.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20030189
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2004
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  • 3
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    Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin–angiotensin system blockade
    Portland Press Ltd. ; 2015
    In:  Clinical Science Vol. 128, No. 8 ( 2015-04-01), p. 483-491
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 128, No. 8 ( 2015-04-01), p. 483-491
    Abstract: The extracellular miRNAs circulate in the bloodstream and may serve as novel diagnostic and therapeutic biomarkers. The aim of the present study was to investigate circulating Toll-like receptor 4 (TLR4)-responsive miRNA expression in patients with coronary artery disease (CAD) and to examine the effects of renin–angiotensin system (RAS) blockade and statins on miRNA levels. This study included 41 patients with CAD and 20 subjects without CAD (non-CAD). Plasma TLR4-responsive miRNA samples were analysed using a microarray assay for 1700 human miRNA. The candidate miRNAs were verified with real-time reverse transcription (RT)-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin [angiotensin II receptor blocker (ARB)] or enalapril and atorvastatin [angiotensin-converting enzyme inhibitor (ACEI)] . Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in seven TLR4-responsive miRNAs between the CAD and non-CAD groups (P & lt;0.05). Real-time PCR verified that miR-31, miR-181a, miR-16 and miR-145 were significantly lower in the CAD group than in the non-CAD group (P & lt;0.01). Levels of TLR4 protein were higher in the CAD group than in the non-CAD group (P & lt;0.01) and were negatively correlated with levels of TLR4-responsive miRNAs. Receiver operating characteristic (ROC) curve analysis revealed that a panel of these four miRNAs was sensitive and specific enough to distinguish CAD from non-CAD [area under the curve (AUC)=0.93, 95% CI (confidence interval)=0.99–0.87]. Both ARB and ACEI groups showed increased TLR4-responsive miRNAs and diminished levels of TLR4 protein (P & lt;0.05). Changes in miRNAs and TLR4 levels were greater in the ARB group than in the ACEI group (P & lt;0.05). Circulating TLR4-responsive miRNAs including miR-31, miR-181a, miR-16 and miR-145 were significantly lower in patients with CAD compared with controls and these miRNAs may be involved in the pathogenesis of CAD.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20140417
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2015
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  • 4
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    Renal, haemodynamic and hormonal interactions between atrial natriuretic factor and arginine vasopressin in patients with congestive heart failure
    Portland Press Ltd. ; 1992
    In:  Clinical Science Vol. 82, No. 4 ( 1992-04-01), p. 363-368
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 82, No. 4 ( 1992-04-01), p. 363-368
    Abstract: 1. Nine patients with compensated heart failure were infused with synthetic arginine vasopressin at a rate of 0.1 m-units min−1 kg−1 for 60 min to increase their plasma arginine vasopressin concentration. Synthetic human atrial natriuretic factor (3 pmol min−1 kg−1) or placebo was co-infused with the arginine vasopressin in random order in a single-blind cross-over design. 2. The resultant plasma concentrations of arginine vasopressin and atrial natriuretic factor fell to within the upper range observed in congestive heart failure. Compared with the infusion of arginine vasopressin alone, atrial natriuretic factor co-infusion enhanced both the urine flow rate and the sodium excretion rate (both P & lt; 0.05) without significant haemodynamic and hormonal effects. 3. Systematic blood pressure was elevated by arginine vasopressin infusion (P & lt; 0.05) without any change in heart rate. Co-infusion of atrial natriuretic factor did not affect these haemodynamic parameters. 4. These results suggest that an increased release of atrial natriuretic factor maintains water and sodium excretion in the presence of arginine vasopressin-induced renal modulations, and that the pressor effect of arginine vasopressin is not antagonized by the increased plasma level of atrial natriuretic factor in patients with congestive heart failure.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/cs0820363
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1992
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  • 5
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    Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart
    Portland Press Ltd. ; 2002
    In:  Clinical Science Vol. 102, No. 4 ( 2002-4-1), p. 381-
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 102, No. 4 ( 2002-4-1), p. 381-
    Type of Medium: Online Resource
    ISSN: 0143-5221
    URL: Article
    DOI: 10.1042/CS20010219
    Language: Unknown
    Publisher: Portland Press Ltd.
    Publication Date: 2002
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  • 6
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    Expression of Toll-like receptor 4 is associated with enteroviral replication in human myocarditis
    Portland Press Ltd. ; 2003
    In:  Clinical Science Vol. 104, No. 6 ( 2003-06-01), p. 577-584
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 104, No. 6 ( 2003-06-01), p. 577-584
    Abstract: Previous studies have demonstrated that inflammatory cytokine expression associated with enteroviral (EV) infection may play an important role in human myocarditis. However, the mechanism of the host immune response against viral pathogens has not been fully understood. The aim of the present study was to determine whether Toll-like receptor 4 (TLR4) and EV RNA are present in human myocarditis. Endomyocardial biopsy samples were obtained from 44 patients with myocarditis and five controls. Levels of plus- and minus-strand EV RNAs and TLR4 mRNA were measured by real-time reverse transcriptase–PCR. Immunohistochemical analysis was performed to identify the cellular source of TLR4 and the EV capsid protein VP1. EV RNA was present in 21 patients with myocarditis and these patients were defined as having either active viral replication (n=15) or latent viral persistence (n=6). Neither strand of EV RNA was detected in controls. TLR4 mRNA expression levels were higher in myocarditis patients than in controls (TLR4/glyceraldehyde-3-phosphate dehydrogenase ratio 1.48±0.17 compared with 0.08±0.06, P & lt;0.001). A positive correlation was found between EV RNA and TLR4 levels (plus-strand vs TLR4: r=0.66, P & lt;0.001; minus-strand vs TLR4: r=0.48, P & lt;0.001). TLR4 immunostaining was observed in infiltrating cells and myocytes in patients with myocarditis. The EV capsid protein VP1 was also found in myocytes. The myocarditis group with EV replication and high levels of TLR4 showed significantly lower systolic function. The present study has shown that increased expression of TLR4 is associated with EV replication and that these RNA levels are related to cardiac dysfunction in human myocarditis.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20020263
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2003
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  • 7
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    Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart
    Portland Press Ltd. ; 2002
    In:  Clinical Science Vol. 102, No. 4 ( 2002-04-01), p. 381-386
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 102, No. 4 ( 2002-04-01), p. 381-386
    Abstract: The pathway of tissue aldosterone production may exist in the heart, and may be an important contributory factor to myocardial fibrosis and cardiac remodelling in the failing heart. CYP11B2 (aldosterone synthase) catalyses the final step of aldosterone production. The aim of the present study was to determine whether CYP11B2 and CYP11B1 (11β-hydroxylase) are expressed in myocardial tissues, and whether these enzymes contribute to collagen accumulation and myocardial dysfunction in the failing human heart. Endomyocardial tissues were obtained from 23 patients with chronic heart failure (CHF) and 10 controls. CYP11B2 and CYP11B1 mRNA levels were measured by real-time quantitative reverse transcriptase-PCR. The myocardial collagen volume fraction (CVF) was determined by digital planimetry. CYP11B2 mRNA expression was greater in the CHF group than in the controls (P 〈 0.05), while CYP11B1 mRNA was barely expressed in either group. There was a positive correlation between CYP11B2 mRNA levels and CVF (r = 0.64, P =0.001). CYP11B2 mRNA was particularly highly expressed in subgroups of CHF patients with a large left ventricular end-systolic diameter ( 〉 55mm) or a low left ventricular ejection fraction ( 〈 30%). CYP11B2 mRNA expression and CVF were lower in a CHF subgroup treated with a combination of spironolactone and angiotensin-converting enzyme inhibitors (ACEIs) than in a subgroup not treated with these drugs. In conclusion, this study has shown that increased myocardial expression of CYP11B2 mRNA is associated with increased myocardial fibrosis and with the severity of left ventricular dysfunction in human CHF. In addition, CYP11B2 expression and cardiac fibrosis are found to be decreased in CHF patients on drug therapy comprising spironolactone combined with ACEIs.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/cs1020381
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2002
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  • 8
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    Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease
    Portland Press Ltd. ; 2017
    In:  Clinical Science Vol. 131, No. 15 ( 2017-08-01), p. 2007-2017
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 131, No. 15 ( 2017-08-01), p. 2007-2017
    Abstract: Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a, low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9–14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20170242
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2017
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  • 9
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    Expression of miR-146a/b is associated with the Toll-like receptor 4 signal in coronary artery disease: effect of renin–angiotensin system blockade and statins on miRNA-146a / b and Toll-like receptor 4 levels
    Portland Press Ltd. ; 2010
    In:  Clinical Science Vol. 119, No. 9 ( 2010-10-01), p. 395-405
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 119, No. 9 ( 2010-10-01), p. 395-405
    Abstract: The TLR4 (Toll-like receptor 4) signal plays an important role in immunity in CAD (coronary artery disease). miR-146a/b (where miR is microRNA) regulates the TLR4 downstream molecules IRAK1 (interleukin-1-receptor-associated kinase 1) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6). It has also been reported that statins and RAS (renin–angiotensin system) inhibition and have anti-atherosclerotic properties. In the present study, we have investigated whether miR-146a/b was expressed with the TLR4 signal in CAD patients, and whether combined treatment with a statin and RAS inhibition might affect these levels. A total of 66 patients with CAD and 33 subjects without CAD (non-CAD) were enrolled. Patients with CAD were randomized to 12 months of combined treatment with atorvastatin and telmisartan [an ARB (angiotensin II receptor blocker)] or atorvastatin and enalapril [an ACEI (angiotensin-converting enzyme inhibitor)] . PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 12 months. Levels of miR-146a/b, IRAK1 mRNA, TRAF6 mRNA and TLR4 mRNA/TLR4 protein were significantly higher in the CAD group than in the non-CAD group (all P & lt;0.01). Levels of miR-146a/b were positively correlated with IRAK1 mRNA and TRAF6 mRNA levels. After 12 months of treatment, these levels were markedly decreased in the ARB and ACEI groups, with the decrease in the ARB group being greater than that in the ACEI group (all P & lt;0.05). In our 12-month follow-up study, high levels of miR-146a and TLR4 mRNA/TLR4 protein at baseline were independent predictors of cardiac events. The present study demonstrates that combined treatment with an ARB and a statin decreases miR-146a/b and the TLR4 signal in CAD patients, possibly contributing to the anti-atherogenic effects of ARBs and statins in this disorder.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20100003
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2010
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  • 10
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    NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin
    Portland Press Ltd. ; 2014
    In:  Clinical Science Vol. 126, No. 3 ( 2014-02-01), p. 233-241
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 126, No. 3 ( 2014-02-01), p. 233-241
    Abstract: The NLRP-3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The aim of the present study was to determine whether NLRP3 inflammasome is expressed in patients with CAD (coronary artery disease) and whether statins (atorvastatin or rosuvastatin) might affect NLRP3 levels. In an in vitro study, human THP-1 cells treated with statins were analysed for NLRP3 inflammasome levels. The present study included 60 patients with CAD and 30 subjects without CAD (non-CAD). Patients with CAD randomly received either 8 months of treatment with atorvastatin or rosuvastatin. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 8 months of statin therapy. Levels of NLRP3 inflammasome, IL (interleukin)-1β and IL-18 were measured by real-time RT–PCR (reverse transcription–PCR) and FACS. Levels of NLRP3 inflammasome were higher in the CAD group than in the non-CAD group. There was a positive correlation between NLRP3 inflammasome and cytokines (IL-1β and IL-18) levels. A randomized clinical study has shown that atorvastatin markedly diminished NLRP3 inflammasome levels, whereas rosuvastatin had no impact on these levels. Levels of NLRP3 inflammasome decreased in THP-1 cells treated with statins compared with those treated with vehicle, and the fold changes in NLRP3 inflammasome were higher in THP-1 cells treated with atorvastatin compared with those treated with rosuvastatin. The present study suggests that atorvastatin down-regulates NLRP3 inflammasome expression in CAD, possibly contributing to the inhibitory effects of atorvastatin on chronic inflammation and atherogenic progression in this disorder.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20130043
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2014
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