| 1. |
- Jatta, Ken, et al.
(författare)
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Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease
- 2009
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Ingår i: Journal of Clinical Pathology. - London : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 62:1, s. 70-76
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Tidskriftsartikel (refereegranskat)abstract
- Background/aim: A Significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation which have been correlated to increased mortality. The current study aimed to determine the molecular mechanisms mediating decreased capillary formation in COPD.Methods: Twenty-four COPD patients and twelve matching controls were recruited. COPD patients were divided into mild, moderate and severe groups according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Skeletal muscle biopsies were obtained from the tibialis anterior muscle. Fibre typing and capillary formation together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF-1á and HIF-3á ), vascular endothelial growth factors (VEGF-A, -B and -C isoforms) and von Hippel Lindau (VHL) were determined. VHL expression and localization was further studied by immunohistochemistry.Results: Skeletal muscle capillary formation was significantly decreased with ascending disease severity. Compared to controls, a tendency to mRNA overexpression of HIF-1á, HIF-3á and VEGF isoforms was observed at mild and moderate COPD that decreased at the severe stage. By contrast, skeletal muscle biopsies from COPD patients exhibited significant overexpression of VHL both on the mRNA and protein levels by immunohistochemistry. VHL protein was further determined to be localized to satellite cells.Conclusions: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may exert a negative impact on transducing the hypoxic signal and may contribute to decreased capillarization in skeletal muscles of patients with COPD.
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| 2. |
- Antoniewicz, Lukasz, et al.
(författare)
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Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers
- 2016
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 255, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The use of electronic cigarettes is increasing dramatically on a global scale and its effects on human health remain uncertain. In the present study, we measured endothelial progenitor cells (EPCs) and microvesicles (MVs) in healthy young volunteers following short-term exposure to inhalation of e-cigarette vapor (ECV) to determine vascular changes.Methods: Sixteen healthy seldom smokers were randomized into two groups either exposed or not exposed to 10 puffs of ECV for 10 min, in a crossover design. Blood samples were obtained at baseline and 1, 4 and 24 h following exposure. EPCs (CD34 + CD309) and MVs were analyzed by flow cytometry. MVs were phenotyped according to origin (platelet (CD41), endothelial (CD144), leukocytes (CD45), monocytes (CD14)) and nuclear content (SYTO 13 dye). In addition, expression of inflammation markers such P-selectin (CD62P), E-selectin (CD62E), CD40-ligand (CD154) and HMGB1 was investigated. Fractional exhaled nitric oxide (FeNO) was also measured at baseline and after 24 h.Results: EPC levels in blood were significantly increased 1 h following exposure to ECV and returned to baseline values after 24 h. Only E-selectin positive MVs (endothelial origin) were slightly elevated (p < 0.038). FeNO was unaffected by exposure to ECV. Conclusions: In healthy volunteers, ten puffs of e-cigarette vapor inhalation caused an increase in EPCs. This increase was of the same magnitude as following smoking of one traditional cigarette, as we previously demonstrated. Taken together, these results may represent signs of possible vascular changes after short e-cigarette inhalation. Further studies analyzing potential cardiovascular health effects are critical as the e-cigarette market continues to burgeon.
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| 3. |
- Basic, Vladimir T., 1982-, et al.
(författare)
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Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cigarette smoke (CS) is a well established risk factor in the development of COPD and irreversible airflow limitation. In contrast, the extent to which CS exposure contributes to development of peripheral skeletal muscle dysfunction and wasting remains largely unknown. Decline in skeletal muscle regenerative capacity has been previously reported in COPD patients.Methods: To investigate effects of chronic CS exposure on skeletal muscle regenerative capacity, 129/SvJ mice were exposed to CS for 6 months. The expression levels of myogenin, Jarid2, Znf496, Notch1, Pax7, Fgf1 and Myh3, which are known to regulate skeletal muscle myogenesis, were studied. Additionally, number of fibers with central nuclei, myonuclei number and mean fiber cross-sectional area were assessed.Results: Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly decreased expression of Jarid2, coupled with enhanced expression of Znf496, Notch1, Pax7, Fgf1 and Myh3. Expression of myogenin, a marker of terminally differentiated myofibers, was reduced. Furthermore, reduced muscle fiber crosssectional area, increased number of fibers with central nuclei and reduced myonuclei number were also observed in CS-exposed animals.Conclusions: Taken together, current results provide evidence linking chronic CS exposure and an ongoing damage/repair process as well as impaired regenerative capacity in skeletal muscles of CS-exposed mice.
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| 4. |
- Basic, Vladimir T., et al.
(författare)
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Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.
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| 5. |
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| 6. |
- Basic, Vladimir Tomislav, et al.
(författare)
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Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
- 2012
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Ingår i: American Journal of Physiology - Lung cellular and Molecular Physiology. - Bethesda, USA : American Physiological Society. - 1040-0605 .- 1522-1504. ; 303:6, s. L519-L527
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.
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| 7. |
- Bitar, Milad S., et al.
(författare)
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Inflammation and apoptosis in aortic tissues of aged type II diabetes : Amelioration with alpha-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism
- 2010
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Ingår i: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 86:23-24, s. 844-853
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Endothelial dysfunction is a key triggering event in the development of cardiovascular diseases and the current study explored this phenomenon in the context of inflammation, apoptosis, reactive oxygen species (ROS) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway during chronic diabetes. Main methods: alpha-Lipoic acid (ALA) and wortmannin (WM) were chronically administered to aged Goto Kakizaki (GK) rats, a genetic model of non-obese type II diabetes. Key indices of inflammation, apoptosis and oxidative stress were assessed using western blotting, real-time PCR and immunofluoresence-based techniques. Key findings: A chronic inflammation (e.g., increased mRNA/protein levels of INF-alpha, ICAM, fractalkine, CD-68, myeloperoxidase) in connection with increased caspase-based apoptotic cell death and heightened state of oxidative stress (HSOS)- appear to exist in diabetic cardiovascular tissues. An assessment of NF-kappa B dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of I kappa B-alpha, NIK, IRK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-kappa B-DNA binding activity. Most of the aforementioned cardiovascular-based diabetic abnormalities including reduced activities of PI3K and Akt kinase were ameliorated following chronic ALA therapy. WM, given to GK rats negated the anti-inflammatory and anti-apoptotic actions of ALA. Significance: Our data highlight a unifying mechanism whereby HSOS through an induction of NF-kappa B activity together with an impairment in PI3K/Akt pathway favors pro-inflammatory/pro-apoptotic diabetic vascular milieu that culminate in the onset of endothelial dysfunction, a phenomenon which appears to be amenable to treatment with antioxidants and/or PI3/Akt mimetics (e.g., ALA).
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| 8. |
- Eliason, Gabriella, 1975-, et al.
(författare)
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Alterations in the muscle-to-capillary interface in patients with different degrees of chronic obstructive pulmonary disease
- 2010
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Ingår i: Respiratory Research. - London, United Kingdom : BioMed Central. - 1465-9921 .- 1465-993X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is hypothesized that decreased capillarization of limb skeletal muscle is implicated in the decreased exercise tolerance in COPD patients. We have recently demonstrated decreased number of capillaries per muscle fibre (CAF) but no changes in CAF in relation to fibre area (CAFA), which is based on the diffusion distance between the capillary and muscle fibre. The aim of the current study is to investigate the muscle-to-capillary interface which is an important factor involved in oxygen supply to the muscle that has previously been suggested to be a more sensitive marker for changes in the capillary bed compared to CAF and CAFA.Methods: 23 COPD patients and 12 age-matched healthy subjects participated in the study. Muscle-to-capillary interface was assessed in muscle biopsies from the tibialis anterior muscle using the following parameters:1) The capillary-to-fibre ratio (C:Fi) which is defined as the sum of the fractional contributions of all capillary contacts around the fibre2) The ratio between C:Fi and the fibre perimeter (CFPE-index)3) The ratio between length of capillary and fibre perimeter (LC/PF) which is also referred to as the index of tortuosity.Exercise capacity was determined using the 6-min walking test. Results: A positive correlation was found between CFPE-index and ascending disease severity with CFPE-index for type I fibres being significantly lower in patients with moderate and severe COPD. Furthermore, a positive correlation was observed between exercise capacity and CFPE-index for both type I and type IIa fibres.Conclusion: It can be concluded that the muscle-to-capillary interface is disturbed in the tibialis anterior muscle in patients with COPD and that interface is strongly correlated to increased disease severity and to decreased exercise capacity in this patient group.
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| 9. |
- Krivospitskaya, Olesya, 1983-, et al.
(författare)
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A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
- 2012
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Ingår i: Molecular Medicine. - New York, USA : The Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 18:1, s. 712-718
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Tidskriftsartikel (refereegranskat)abstract
- All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.
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