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1.  Circulating concentrations of GLP-1 are associated with coronary atherosclerosis in humans 
Background
GLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study.
Methods
GLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain.
Results
GLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 – 6.08; p = 0.03).
Conclusion
Circulating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.
doi:10.1186/1475-2840-12-117
PMCID: PMC3765863  PMID: 23953602
GLP-1; Atherosclerosis; Coronary CT angiography
2.  Expression of Human Chemerin Induces Insulin Resistance in the Skeletal Muscle but Does Not Affect Weight, Lipid Levels, and Atherosclerosis in LDL Receptor Knockout Mice on High-Fat Diet 
Diabetes  2010;59(11):2898-2903.
OBJECTIVE
Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo.
RESEARCH DESIGN AND METHODS
We used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet.
RESULTS
Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5′AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue.
CONCLUSIONS
Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.
doi:10.2337/db10-0362
PMCID: PMC2963549  PMID: 20724582
3.  Novel AAV serotypes for improved ocular gene transfer 
The journal of gene medicine  2008;10(4):375-382.
Some of the most successful gene therapy results have been obtained using recombinant viral vectors to treat animal models of inherited and acquired ocular diseases. Clinical trials using adenovirus vector systems have been initiated for two ocular diseases. Adeno-associated viruses (AAVs) represent an attractive alternative to adenoviral vector systems as they enable stable and long-term expression and can target a variety of different ocular cell types depending on the capsid serotype; recently clinical trails for congenital blindness was initiated with a vector-based AAV serotype 2. High levels of retinal gene transfer have been achieved using vectors based on AAV serotypes 1, 2, 4 and 5. This report compares the gene transfer efficacy and stability of expression of vector systems based on three novel AAV serotypes: AAV7, 8, 9, with the established vectors AAV1, 2, 5. We show here that AAV7 and 8 enable superior long-term transduction of retinal and also anterior chamber structures.
doi:10.1002/jgm.1126
PMCID: PMC2842078  PMID: 18278824
adeno-associated virus; novel serotypes; ocular gene transfer
4.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Background
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
Methods
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
Results
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
Conclusion
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
doi:10.1186/1475-2840-8-50
PMCID: PMC2754422  PMID: 19751510
5.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Background
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Conclusions/Significance
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
doi:10.1371/journal.pone.0004733
PMCID: PMC2649379  PMID: 19266101
6.  Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent 
Background
The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice – a model which is most adequately mimicking the clinical setting.
Methods and results
Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-IM or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic en face analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-IM by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.
Conclusion
Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.
doi:10.1186/1475-2840-6-15
PMCID: PMC1868709  PMID: 17475009
7.  An angiogenic role for the human peptide antibiotic LL-37/hCAP-18 
Journal of Clinical Investigation  2003;111(11):1665-1672.
Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor–like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.
doi:10.1172/JCI200317545
PMCID: PMC156109  PMID: 12782669

Results 1-7 (7)