1
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Lan Y, Peng Q, Shen J, Liu H. Elucidating common biomarkers and pathways of osteoporosis and aortic valve calcification: insights into new therapeutic targets. Sci Rep 2024; 14:27827. [PMID: 39537712 PMCID: PMC11560947 DOI: 10.1038/s41598-024-78707-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Osteoporosis and aortic valve calcification, prevalent in the elderly, have unclear common mechanisms. This study aims to uncover them through bioinformatics analysis. METHODS Microarray data from GEO was analyzed for osteoporosis and aortic valve calcification. Differential expression analysis identified co-expressed genes. SVM-RFE and random forest selected key genes. GO and KEGG enrichment analyses were performed. Immunoinfiltration and GSEA analyses were subsequently performed. NetworkAnalyst analyzed microRNAs/TFs. HERB predicted drugs, and molecular docking assessed targeting potential. RESULTS Thirteen genes linked to osteoporosis and aortic valve calcification were identified. TNFSF11, KYNU, and HLA-DMB emerged as key genes. miRNAs, TFs, and drug predictions offered therapeutic insights. Molecular docking suggested 17-beta-estradiol and vitamin D3 as potential treatments. CONCLUSION The study clarifies shared mechanisms of osteoporosis and aortic valve calcification, identifies biomarkers, and highlights TNFSF11, KYNU, and HLA-DMB. It also suggests 17-beta-estradiol and vitamin D3 as potential effective treatments.
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Affiliation(s)
- Yujian Lan
- School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Qingping Peng
- School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jianlin Shen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China.
- Central Laboratory, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China.
| | - Huan Liu
- Department of Orthopaedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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2
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Chen C, Ding Y, Huang Q, Zhang C, Zhao Z, Zhou H, Li D, Zhou G. Relationship between arginine methylation and vascular calcification. Cell Signal 2024; 119:111189. [PMID: 38670475 DOI: 10.1016/j.cellsig.2024.111189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
In patients on maintenance hemodialysis (MHD), vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD), which is the primary cause of death in chronic kidney disease (CKD). The main component of VC in CKD is the vascular smooth muscle cells (VSMCs). VC is an ordered, dynamic activity. Under the stresses of oxidative stress and calcium-‑phosphorus imbalance, VSMCs undergo osteogenic phenotypic transdifferentiation, which promotes the formation of VC. In addition to traditional epigenetics like RNA and DNA control, post-translational modifications have been discovered to be involved in the regulation of VC in recent years. It has been reported that the process of osteoblast differentiation is impacted by catalytic histone or non-histone arginine methylation. Its function in the osteogenic process is comparable to that of VC. Thus, we propose that arginine methylation regulates VC via many signaling pathways, including as NF-B, WNT, AKT/PI3K, TGF-/BMP/SMAD, and IL-6/STAT3. It might also regulate the VC-related calcification regulatory factors, oxidative stress, and endoplasmic reticulum stress. Consequently, we propose that arginine methylation regulates the calcification of the arteries and outline the regulatory mechanisms involved.
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Affiliation(s)
- Chen Chen
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Yuanyuan Ding
- Department of Pain Management, Shengjing Hospital, China Medical University, China
| | - Qun Huang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Chen Zhang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Zixia Zhao
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Hua Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Detian Li
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Guangyu Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China.
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Wu PY, Lee SY, Chang KV, Chao CT, Huang JW. Gender-Related Differences in Chronic Kidney Disease-Associated Vascular Calcification Risk and Potential Risk Mediators: A Scoping Review. Healthcare (Basel) 2021; 9:979. [PMID: 34442116 PMCID: PMC8394860 DOI: 10.3390/healthcare9080979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
Vascular calcification (VC) involves the deposition of calcium apatite in vascular intima or media. Individuals of advanced age, having diabetes mellitus or chronic kidney disease (CKD) are particularly at risk. The pathogenesis of CKD-associated VC evolves considerably. The core driver is the phenotypic change involving vascular wall constituent cells toward manifestations similar to that undergone by osteoblasts. Gender-related differences are observed regarding the expressions of osteogenesis-regulating effectors, and presumably the prevalence/risk of CKD-associated VC exhibits gender-related differences as well. Despite the wealth of data focusing on gender-related differences in the risk of atherosclerosis, few report whether gender modifies the risk of VC, especially CKD-associated cases. We systematically identified studies of CKD-associated VC or its regulators/modifiers reporting data about gender distributions, and extracted results from 167 articles. A significantly higher risk of CKD-associated VC was observed in males among the majority of original investigations. However, substantial heterogeneity exists, since multiple large-scale studies yielded neutral findings. Differences in gender-related VC risk may result from variations in VC assessment methods, the anatomical segments of interest, study sample size, and even the ethnic origins of participants. From a biological perspective, plausible mediators of gender-related VC differences include body composition discrepancies, alterations involving lipid profiles, inflammatory severity, diversities in matrix Gla protein (MGP), soluble Klotho, vitamin D, sclerostin, parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23), and osteoprotegerin levels. Based on our findings, it may be inappropriate to monotonously assume that male patients with CKD are at risk of VC compared to females, and we should consider more background in context before result interpretation.
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Affiliation(s)
- Patrick Yihong Wu
- School of Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan;
| | - Szu-Ying Lee
- Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County 640, Taiwan; (S.-Y.L.); (J.-W.H.)
| | - Ke-Vin Chang
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital BeiHu Branch, Taipei 10845, Taiwan;
| | - Chia-Ter Chao
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100233, Taiwan
- Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan
- Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital BeiHu Branch, Taipei 10845, Taiwan
| | - Jenq-Wen Huang
- Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County 640, Taiwan; (S.-Y.L.); (J.-W.H.)
- Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan
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4
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Chinetti G, Neels JG. Roles of Nuclear Receptors in Vascular Calcification. Int J Mol Sci 2021; 22:6491. [PMID: 34204304 PMCID: PMC8235358 DOI: 10.3390/ijms22126491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022] Open
Abstract
Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.
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Affiliation(s)
- Giulia Chinetti
- Université Côte d’Azur, CHU, INSERM, C3M, 06204 Nice, France;
| | - Jaap G. Neels
- Université Côte d’Azur, INSERM, C3M, 06204 Nice, France
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5
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Woodward HJ, Zhu D, Hadoke PWF, MacRae VE. Regulatory Role of Sex Hormones in Cardiovascular Calcification. Int J Mol Sci 2021; 22:4620. [PMID: 33924852 PMCID: PMC8125640 DOI: 10.3390/ijms22094620] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.
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Affiliation(s)
- Holly J. Woodward
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK;
| | - Dongxing Zhu
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Patrick W. F. Hadoke
- University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK;
| | - Victoria E. MacRae
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK;
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Regulation of Vascular Calcification by Reactive Oxygen Species. Antioxidants (Basel) 2020; 9:antiox9100963. [PMID: 33049989 PMCID: PMC7599480 DOI: 10.3390/antiox9100963] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/18/2022] Open
Abstract
Vascular calcification is the deposition of hydroxyapatite crystals in the medial or intimal layers of arteries that is usually associated with other pathological conditions including but not limited to chronic kidney disease, atherosclerosis and diabetes. Calcification is an active, cell-regulated process involving the phenotype transition of vascular smooth muscle cells (VSMCs) from contractile to osteoblast/chondrocyte-like cells. Diverse triggers and signal transduction pathways have been identified behind vascular calcification. In this review, we focus on the role of reactive oxygen species (ROS) in the osteochondrogenic phenotype switch of VSMCs and subsequent calcification. Vascular calcification is associated with elevated ROS production. Excessive ROS contribute to the activation of certain osteochondrogenic signal transduction pathways, thereby accelerating osteochondrogenic transdifferentiation of VSMCs. Inhibition of ROS production and ROS scavengers and activation of endogenous protective mechanisms are promising therapeutic approaches in the prevention of osteochondrogenic transdifferentiation of VSMCs and subsequent vascular calcification. The present review discusses the formation and actions of excess ROS in different experimental models of calcification, and the potential of ROS-lowering strategies in the prevention of this deleterious condition.
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7
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A Timing Effect of 17-β Estradiol on Atherosclerotic Lesion Development in Female ApoE -/- Mice. Int J Mol Sci 2020; 21:ijms21134710. [PMID: 32630298 PMCID: PMC7369926 DOI: 10.3390/ijms21134710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/25/2020] [Accepted: 06/29/2020] [Indexed: 11/18/2022] Open
Abstract
Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17β-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0–3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.
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Abstract
PURPOSE OF REVIEW This review addresses recent developments in studies of lipid regulation of calcific disease of arteries and cardiac valves, including the role of nuclear receptors. The role of lipid-soluble signals and their receptors is timely given the recent evidence and concerns that lipid-lowering treatment may increase the rate of progression of coronary artery calcification, which has been long associated with increased cardiovascular risk. Understanding the mechanisms will be important for interpreting such clinical information. RECENT FINDINGS New findings support regulation of calcific vascular and valvular disease by nuclear receptors, including the vitamin D receptor, glucocorticoid receptor, nutrient-sensing nuclear receptors (liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors), and sex hormone (estrogen and androgen) receptors. There were two major unexpected findings: first, vitamin D supplementation, which was previously believed to prevent or reduce vascular calcification, showed no cardiovascular benefit in large randomized, controlled trials. Second, both epidemiological studies and coronary intravascular ultrasound studies suggest that treatment with HMG-CoA reductase inhibitors increases progression of coronary artery calcification, raising a question of whether there are mechanically stable and unstable forms of coronary calcification. SUMMARY For clinical practice and research, these new findings offer new fundamental mechanisms for vascular calcification and provide new cautionary insights for therapeutic avenues.
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Affiliation(s)
- Tamer Sallam
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095-1679
| | - Yin Tintut
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095-1679
| | - Linda L. Demer
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095-1679
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095-1679
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9
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Kamenskiy A, Poulson W, Sim S, Reilly A, Luo J, MacTaggart J. Prevalence of Calcification in Human Femoropopliteal Arteries and its Association with Demographics, Risk Factors, and Arterial Stiffness. Arterioscler Thromb Vasc Biol 2018; 38:e48-e57. [PMID: 29371245 DOI: 10.1161/atvbaha.117.310490] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 01/15/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Arterial calcification and stiffening increase the risk of reconstruction failure, amputation, and mortality in patients with peripheral arterial disease, but underlying mechanisms and prevalence are unclear. APPROACH AND RESULTS Fresh human femoropopliteal arteries were obtained from n=431 tissue donors aged 13 to 82 years (mean age, 53±16 years) recording the in situ longitudinal prestretch. Arterial diameter, wall thickness, and opening angles were measured optically, and stiffness was assessed using planar biaxial extension and constitutive modeling. Histological features were determined using transverse and longitudinal Verhoeff-Van Gieson and Alizarin stains. Medial calcification was quantified using a 7-stage grading scale and was correlated with structural and mechanical properties and clinical characteristics. Almost half (46%) of the femoropopliteal arteries had identifiable medial calcification. Older arteries were more calcified, but small calcium deposits were observed in arteries as young as 18 years old. After controlling for age, positive correlations were observed between calcification, diabetes mellitus, dyslipidemia, and body mass index. Tobacco use demonstrated a negative correlation. Calcified arteries were larger in diameter but had smaller circumferential opening angles. They were also stiffer longitudinally and circumferentially and had thinner tunica media and external elastic lamina with more discontinuous elastic fibers. CONCLUSIONS Although aging is the dominant risk factor for femoropopliteal artery calcification and stiffening, these processes seem to be linked and can begin at a young age. Calcification is associated with the presence of certain risk factors and with elastic fiber degradation, suggesting overlapping molecular pathways that require further investigation.
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Affiliation(s)
- Alexey Kamenskiy
- From the Department of Surgery, University of Nebraska Medical Center, Omaha.
| | - William Poulson
- From the Department of Surgery, University of Nebraska Medical Center, Omaha
| | - Sylvie Sim
- From the Department of Surgery, University of Nebraska Medical Center, Omaha
| | - Austin Reilly
- From the Department of Surgery, University of Nebraska Medical Center, Omaha
| | - Jiangtao Luo
- From the Department of Surgery, University of Nebraska Medical Center, Omaha
| | - Jason MacTaggart
- From the Department of Surgery, University of Nebraska Medical Center, Omaha.
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Hortells L, Sosa C, Millán Á, Sorribas V. Critical Parameters of the In Vitro Method of Vascular Smooth Muscle Cell Calcification. PLoS One 2015; 10:e0141751. [PMID: 26554928 PMCID: PMC4640663 DOI: 10.1371/journal.pone.0141751] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 10/13/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Vascular calcification (VC) is primarily studied using cultures of vascular smooth muscle cells. However, the use of very different protocols and extreme conditions can provide findings unrelated to VC. In this work we aimed to determine the critical experimental parameters that affect calcification in vitro and to determine the relevance to calcification in vivo. EXPERIMENTAL PROCEDURES AND RESULTS Rat VSMC calcification in vitro was studied using different concentrations of fetal calf serum, calcium, and phosphate, in different types of culture media, and using various volumes and rates of change. The bicarbonate content of the media critically affected pH and resulted in supersaturation, depending on the concentration of Ca2+ and Pi. Such supersaturation is a consequence of the high dependence of bicarbonate buffers on CO2 vapor pressure and bicarbonate concentration at pHs above 7.40. Such buffer systems cause considerable pH variations as a result of minor experimental changes. The variations are more critical for DMEM and are negligible when the bicarbonate concentration is reduced to ¼. Particle nucleation and growth were observed by dynamic light scattering and electron microscopy. Using 2mM Pi, particles of ~200nm were observed at 24 hours in MEM and at 1 hour in DMEM. These nuclei grew over time, were deposited in the cells, and caused osteogene expression or cell death, depending on the precipitation rate. TEM observations showed that the initial precipitate was amorphous calcium phosphate (ACP), which converts into hydroxyapatite over time. In blood, the scenario is different, because supersaturation is avoided by a tightly controlled pH of 7.4, which prevents the formation of PO43--containing ACP. CONCLUSIONS The precipitation of ACP in vitro is unrelated to VC in vivo. The model needs to be refined through controlled pH and the use of additional procalcifying agents other than Pi in order to reproduce calcium phosphate deposition in vivo.
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Affiliation(s)
- Luis Hortells
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Zaragoza, Spain
| | - Cecilia Sosa
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Zaragoza, Spain
| | - Ángel Millán
- Institute of Materials Science of Aragón, CSIC – Universidad de Zaragoza, Zaragoza, Spain
| | - Víctor Sorribas
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Zaragoza, Spain
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11
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Vasuri F, Fittipaldi S, Pasquinelli G. Arterial calcification: Finger-pointing at resident and circulating stem cells. World J Stem Cells 2014; 6:540-551. [PMID: 25426251 PMCID: PMC4178254 DOI: 10.4252/wjsc.v6.i5.540] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 09/08/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
The term ‘‘Stammzelle’’ (stem cells) originally appeared in 1868 in the works of Ernst Haeckel who used it to describe the ancestor unicellular organism from which he presumed all multicellular organisms evolved. Since then stem cells have been studied in a wide spectrum of normal and pathological conditions; it is remarkable to note that ectopic arterial calcification was considered a passive deposit of calcium since its original discovering in 1877; in the last decades, resident and circulating stem cells were imaged to drive arterial calcification through chondro-osteogenic differentiation thus opening the idea that an active mechanism could be at the basis of the process that clinically shows a Janus effect: calcifications either lead to the stabilization or rupture of the atherosclerotic plaques. A review of the literature underlines that 130 years after stem cell discovery, antigenic markers of stem cells are still debated and the identification of the osteoprogenitor phenotype is even more elusive due to tissue degradation occurring at processing and manipulation. It is necessary to find a consensus to perform comparable studies that implies phenotypic recognition of stem cells antigens. A hypothesis is based on the singular morphology and amitotic mechanism of division of osteoclasts: it constitutes the opening to a new approach on osteoprogenitors markers and recognition. Our aim was to highlight all the present evidences of the active calcification process, summarize the different cellular types involved, and discuss a novel approach to discover osteoprogenitor phenotypes in arterial wall.
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12
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Willems BAG, Vermeer C, Reutelingsperger CPM, Schurgers LJ. The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol Nutr Food Res 2014; 58:1620-35. [PMID: 24668744 DOI: 10.1002/mnfr.201300743] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/27/2013] [Accepted: 01/01/2014] [Indexed: 12/20/2022]
Abstract
In the past few decades vitamin K has emerged from a single-function "haemostasis vitamin" to a "multi-function vitamin." The use of vitamin K antagonists (VKA) inevitably showed that the inhibition was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.
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Affiliation(s)
- Brecht A G Willems
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands; VitaK BV, Maastricht University, Maastricht, The Netherlands
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13
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Park K, Ju WC, Yeo JH, Kim JY, Seo HS, Uchida Y, Cho Y. Increased OPG/RANKL ratio in the conditioned medium of soybean-treated osteoblasts suppresses RANKL-induced osteoclast differentiation. Int J Mol Med 2014; 33:178-84. [PMID: 24248634 DOI: 10.3892/ijmm.2013.1557] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 11/06/2013] [Indexed: 11/06/2022] Open
Abstract
Soybean is a major dietary source of isoflavones, particularly daidzein and genistein, which stimulate osteoblastic functions that are initiated by binding to estrogen receptor (ER)-α and ER-β found on osteoblasts. However, coupled with a low expression of ER-α and ER-β in osteoclasts, the inhibitory effects of soy isoflavones on osteoclast differentiation is likely mediated through paracrine factors produced by osteoblasts. Therefore, in this study, we investigated whether soybean can indirectly inhibit osteoclast differentiation through the modulation of osteoclastic factors produced by osteoblasts. Treatment with soybean extracts increased the levels of osteoprotegerin (OPG) and decreased those of receptor activator of nuclear factor-κB ligand (RANKL) in the conditioned medium (CM) of MC3T3-E1 osteoblasts. Subsequently, the RANKL-induced RAW264.7 osteoclast formation was markedly inhibited by treatment with CM collected from MC3T3-E1 osteoblasts incubated with soybean extracts (S-CM). Similarly, S-CM significantly attenuated the RANKL-induced increase in the mRNA and protein levels of matrix metalloproteinase-9 (MMP-9), a potential biomarker gene of osteoclast differentiation, through the suppression of nuclear factor of activated T cells c1 (NFATc1) activation. Of note, a soybean concentration of 0.001 mg/ml further increased the OPG/RANKL ratio compared to treatment with a 0.1 mg/ml soybean concentration and was overall, more effective at inhibiting RANKL-induced osteoclast formation and MMP-9 expression. Taken together, our data demonstrate that treatment with soybean extracts stimulates the secretion of OPG and inhibits that of RANKL, thus inhibiting RANKL-induced osteoclast differentiation through the suppression of NFATc1 activation.
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Affiliation(s)
- Kyungho Park
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Gyeonggi 446-701, Republic of Korea
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Yavropoulou MP, Pikilidou M, Yovos JG. Anti-osteoporotic drugs and vascular calcification: the bidirectional calcium traffic. J Vasc Res 2013; 51:37-49. [PMID: 24280985 DOI: 10.1159/000355204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 08/19/2013] [Indexed: 11/19/2022] Open
Abstract
During the last years, numerous epidemiological studies have demonstrated a direct relationship between vascular calcification and low bone mineral density. This observation is in line with experimental data demonstrating the osteogenic characteristics of calcified arteries. Various common risk factors have been suggested to link vascular calcification and bone loss, including aging, estrogen deficiency, vitamin D and K deficiency, diabetes mellitus, renal failure, smoking, chronic inflammation and oxidative stress. Although the underlying pathogenetic mechanisms are not yet clear, current research is focusing on anti-osteoporotic agents that could potentially affect the deposition of calcium in the arterial wall and thus provide an additional therapeutic strategy in elderly osteoporotic women prone to calcific cardiovascular disease.
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Affiliation(s)
- Maria P Yavropoulou
- Division of Endocrinology and Metabolism, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Zhu D, Mackenzie NCW, Farquharson C, MacRae VE. Mechanisms and clinical consequences of vascular calcification. Front Endocrinol (Lausanne) 2012; 3:95. [PMID: 22888324 PMCID: PMC3412412 DOI: 10.3389/fendo.2012.00095] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 07/17/2012] [Indexed: 12/23/2022] Open
Abstract
Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.
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Affiliation(s)
- Dongxing Zhu
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of EdinburghMidlothian, Scotland, UK
| | - Neil C. W. Mackenzie
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of EdinburghMidlothian, Scotland, UK
| | - Colin Farquharson
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of EdinburghMidlothian, Scotland, UK
| | - Vicky E. MacRae
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of EdinburghMidlothian, Scotland, UK
- *Correspondence: Vicky E. MacRae, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian EH25 9RG, UK. e-mail:
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L-carnitine and taurine synergistically inhibit the proliferation and osteoblastic differentiation of vascular smooth muscle cells. Acta Pharmacol Sin 2010; 31:289-96. [PMID: 20154715 DOI: 10.1038/aps.2009.206] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
AIM To investigate the synergistic action of L-carnitine (LC) and taurine (TAU) on the proliferation and osteoblastic differentiation of vascular smooth muscle cells (VSMCs). METHODS DNA and protein synthesis of VSMCs were assessed using scintillation counting. Alkaline phosphatase (ALP) activity and calcium content were determined to investigate the effects of LC and TAU on the osteoblastic differentiation and mineralization of VSMCs. TAU uptake by VSMCs was assayed. RNA interference was used to down-regulate the expression of the TAU transporter (TAUT) in rat VSMCs. RESULTS LC and TAU synergistically inhibited the proliferation and beta-glycerophosphate (beta-GP)-induced osteoblastic differentiation of VSMCs as evidenced by the decreased [(3)H]thymidine incorporation, ALP activity and calcium deposition. Furthermore, LC stimulated the TAU uptake and TAUT expression in VSMCs. Suppression of TAUT with short hairpin RNA (shRNA) abolished the synergistic action of LC and TAU in VSMCs. CONCLUSION The synergistic inhibitory action of LC and TAU on the proliferation and osteoblastic differentiation of VSMCs is attributable to the up-regulation of TAUT expression and TAU uptake by LC.
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Son BK, Akishita M, Iijima K, Ogawa S, Maemura K, Yu J, Takeyama K, Kato S, Eto M, Ouchi Y. Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem 2010; 285:7537-44. [PMID: 20048160 DOI: 10.1074/jbc.m109.055087] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men. However, little is known about the mechanism underlying the cardioprotective effects of androgens. Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor (AR)-dependent transactivation of growth arrest-specific gene 6 (Gas6), a key regulator of inorganic phosphate (P(i))-induced calcification of vascular smooth muscle cells (VSMC). Testosterone and nonaromatizable androgen dihydrotestosterone inhibited P(i)-induced calcification of human aortic VSMC in a concentration-dependent manner. Androgen inhibited P(i)-induced VSMC apoptosis, an essential process for VSMC calcification. The effects on VSMC calcification were mediated by restoration of P(i)-induced down-regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation. These effects of androgen were blocked by an AR antagonist, flutamide, but not by an estrogen receptor antagonist, ICI 182,780. We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region. Dihydrotestosterone stimulated Gas6 promoter activity, and this effect was abrogated by flutamide and by AR siRNA. Site-specific mutation revealed that the proximal ARE was essential for androgen-dependent transactivation of Gas6. Furthermore, chromatin immunoprecipitation assays demonstrated ligand-dependent binding of the AR to the proximal ARE of Gas6. These results indicate that AR signaling directly regulates Gas6 transcription, which leads to inhibition of vascular calcification, and provides a mechanistic insight into the cardioprotective action of androgens.
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Affiliation(s)
- Bo-Kyung Son
- Department of Geriatric Medicine, the Graduate School of Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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18
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Chen NX, Kircelli F, O'Neill KD, Chen X, Moe SM. Verapamil inhibits calcification and matrix vesicle activity of bovine vascular smooth muscle cells. Kidney Int 2009; 77:436-42. [PMID: 20016465 DOI: 10.1038/ki.2009.481] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Calcium channel activity in vascular smooth muscle cells is a critical component during vascular calcification and formation of matrix vesicles. Here, we examined whether the blockade of L-type calcium channels inhibits these functions. Bovine vascular smooth muscle cells or rat aorta organ cultures were incubated in media known to promote calcification and treated with the L-type calcium channel inhibitors verapamil, nifedipine, or nimodipine. The phenylalkylamine, verapamil, significantly decreased calcification of the vascular smooth muscle cells and rat aorta, in a dose-dependent manner, whereas the dihydropyridines, nifedipine and nimodipine, had no effect. Furthermore, verapamil, but not nifedipine, significantly decreased the alkaline phosphatase activity of bovine vascular smooth muscle cells. Verapamil pretreatment of the cells also inhibited matrix vesicle alkaline phosphatase activity and reduced the ability of these matrix vesicles to subsequently calcify on a type I collagen extracellular matrix scaffold. As L-type channels are blocked by verapamil and dihydropyridines, we suggest that verapamil inhibits vascular smooth muscle mineralization and matrix vesicle activity by mechanisms other than the simple blockade of this calcium channel activity.
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Affiliation(s)
- Neal X Chen
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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19
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20
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McRobb L, Handelsman DJ, Heather AK. Androgen-induced progression of arterial calcification in apolipoprotein E-null mice is uncoupled from plaque growth and lipid levels. Endocrinology 2009; 150:841-8. [PMID: 19176322 DOI: 10.1210/en.2008-0760] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Arterial calcification has prognostic significance for cardiovascular outcomes, but its pathogenesis remains unclear. Calcification increases with age, but its prevalence in men suggests hormonal influence. In this study we analyzed the effect of exogenous androgens on calcification of advanced atherosclerotic lesions in the arterial tree of gonadally intact 34-wk-old male and female apolipoprotein E-null mice. Testosterone (T) increased calcification 3- to 4-fold (P < 0.05) in lesions of the innominate artery and aortic sinus. A nonaromatizable androgen, dihydrotestosterone, also increased lesion calcification in the innominate artery (2.4-fold, P < 0.05) but not the aortic sinus. The androgen-induced effects were independent of sex and occurred despite corresponding reductions in plaque area, the latter correlating inversely with increased serum high-density lipoprotein cholesterol levels. Androgen-induced calcification in the innominate artery was observed with up-regulation of local androgen receptor (AR) expression in response to T and dihydrotestosterone for both males and females but neither androgen influenced innominate artery estrogen receptor (ER)-alpha or -beta expression in either sex. Conversely, T-induced calcification in the aortic sinus was associated with down-regulation of ERalpha but not ERbeta expression in both sexes, whereas androgen-induced AR expression was increased in female but decreased in male mice. This study demonstrates for the first time that calcification of advanced atherosclerotic lesions is an androgen-sensitive process and postulates potential roles for both AR- and ER-mediated pathways in androgen-induced vascular calcification. We demonstrate a novel direct link between vascular calcification and the major male hormone, T, uncoupled from conventional relationships with plaque growth and lipid levels.
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Affiliation(s)
- L McRobb
- The Heart Research Institute, Camperdown, New South Wales, Australia
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21
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Taurine inhibits osteoblastic differentiation of vascular smooth muscle cells via the ERK pathway. Amino Acids 2007; 34:525-30. [DOI: 10.1007/s00726-007-0003-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Accepted: 11/09/2007] [Indexed: 11/25/2022]
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22
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Guzman RJ. Clinical, cellular, and molecular aspects of arterial calcification. J Vasc Surg 2007; 45 Suppl A:A57-63. [PMID: 17544025 PMCID: PMC2435088 DOI: 10.1016/j.jvs.2007.02.049] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2007] [Accepted: 02/17/2007] [Indexed: 11/24/2022]
Abstract
Arterial calcification is a complex and independently regulated process with risk factors similar to those for atherosclerotic occlusive disease. It may develop either within the atherosclerotic intima or in the media. When calcification is found in coronary or lower extremity arteries, it is an independent predictor of cardiovascular events and lower extremity amputation. Recent evidence suggests a role for several endogenous stimulators and inhibitors in the pathogenesis of arterial calcification. Inflammatory mediators and matrix-degrading enzymes are also thought to control the progression of calcification in humans. Current research involves efforts to define the complex interactions between cellular and molecular mediators of arterial calcification.
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Affiliation(s)
- Raul J Guzman
- Department of Surgery, Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, TN 37235, USA.
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23
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Montecucco F, Steffens S, Mach F. The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability? Clin Dev Immunol 2007; 2007:75805. [PMID: 18320012 PMCID: PMC2248226 DOI: 10.1155/2007/75805] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2007] [Accepted: 10/14/2007] [Indexed: 01/22/2023]
Abstract
Atherogenesis is characterized by an intense inflammatory process, involving immune and vascular cells. These cells play a crucial role in all phases of atherosclerotic plaque formation and complication through cytokine, protease, and prothrombotic factor secretion. The accumulation of inflammatory cells and thus high amounts of soluble mediators are responsible for the evolution of some plaques to instable phenotype which may lead to rupture. One condition strongly associated with plaque rupture is calcification, a physiopathological process orchestrated by several soluble factors, including the receptor activator of nuclear factor (NF)kappaB ligand (RANKL)/receptor activator of nuclear factor (NF)kappaB (RANK)/osteoprotegerin (OPG) system. Although some studies showed some interesting correlations with acute ischemic events, at present, more evidences are needed to evaluate the predictive and diagnostic value of serum sRANKL and OPG levels for clinical use. The major limitation is probably the poor specificity of these factors for cardiovascular disease. The identification of tissue-specific isoforms could increase the importance of sRANKL and OPG in predicting calcified plaque rupture and the dramatic ischemic consequences in the brain and the heart.
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Affiliation(s)
- Fabrizio Montecucco
- Division of Cardiology, Foundation for Medical Researches, University Hospital of Geneva, 1211 Geneva, Switzerland.
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24
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Martinovic S, Borovecki F, Miljavac V, Kisic V, Maticic D, Francetic I, Vukicevic S. Requirement of a bone morphogenetic protein for the maintenance and stimulation of osteoblast differentiation. ACTA ACUST UNITED AC 2006; 69:23-36. [PMID: 16609267 DOI: 10.1679/aohc.69.23] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The requirement of a bone morphogenetic protein for the maintenance and stimulation of an osteoblast phenotype was examined using mouse MC3T3-E1 cell cultures. Cells expressed BMP-4 mRNA, which correlated with the stimulation of the osteoblast phenotype. The addition of a BMP-4 specific antibody reduced bone nodules, suggesting that BMP-4 is required for the osteogenic activity of osteoblasts in an autocrine manner. Exogenously added BMP-7 gradually decreased the expression of BMP-4 with a concurrent stimulation of the osteoblast phenotype. Exogenous BMP-7 can therefore substitute for endogenously produced BMP-4 acting as a paracrine factor on osteoblasts. The addition of 17beta estradiol decreased BMP-4 expression but initiated synthesis of BMP-6 mRNA, an endocrine signal for osteoblasts, which also substituted for the lack of endogenous BMP-4, as evidenced by normal bone nodule formation. The addition of dexamethasone and parathyroid hormone did not affect the BMP-4 expression but induced transcripts for BMP-2 and BMP-3, respectively, suggesting that their effects on bone can be in part achieved via the BMP signaling. These experiments support the requirement of a BMP for osteoblast differentiation and function, demonstrating for the first time that a BMP can functionally substitute for another BMP in an autocrine/paracrine manner or mediate a response to an endocrine action on osteoblasts.
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25
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Rosenson RS, Tangney CC, Langman CB, Parker TS, Levine DM, Gordon BR. Short-term reduction in bone markers with high-dose simvastatin. Osteoporos Int 2005; 16:1272-6. [PMID: 16088363 DOI: 10.1007/s00198-005-1897-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2004] [Accepted: 10/10/2004] [Indexed: 10/25/2022]
Abstract
The effect of statins on bone mass and fracture rates is uncertain. Therefore, we investigated whether statin therapy acutely altered bone turnover as measured by changes in bone serum markers (bone-specific alkaline phosphatase, osteocalcin, and type I collagen N-telopeptide cross-links). Fasting blood samples were obtained from 55 (M/F 39/16) healthy nonsmoking adults (mean +/- standard deviation: age, 50.4+/-7.5 years; body mass index, 27.8+/-4.9 kg/m(2)) with low-density lipoprotein cholesterol concentrations between 3.38-4.90 mmol/l. Subjects were randomized to four possible 8-week treatment regimens: placebo (n =14), pravastatin 40 mg/daily (n =12), simvastatin 20 mg/daily (n =14) or simvastatin 80 mg/daily (n =15). High-dose simvastatin (80 mg/daily) produced a significant reduction in bone-specific alkaline phosphatase as compared with other treatment regimens (p =0.009). However, there were no changes in urinary N-telopeptide cross-links, a sensitive marker of bone resorption. Short-term use of high-dose simvastatin lowers the level of the serum bone marker bone-specific alkaline phosphatase, which suggests the possibility of reduced bone turnover.
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Affiliation(s)
- Robert S Rosenson
- Preventive Cardiology Center, Division of Cardiology, Departments of Medicine and Preventive Medicine, Northwestern University, Feinberg School of Medicine, 301 E. Huron Street, Galter Pavilion, Chicago, IL 60611, USA.
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26
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Rzewuska-Lech E, Jayachandran M, Fitzpatrick LA, Miller VM. Differential effects of 17beta-estradiol and raloxifene on VSMC phenotype and expression of osteoblast-associated proteins. Am J Physiol Endocrinol Metab 2005; 289:E105-12. [PMID: 15713688 DOI: 10.1152/ajpendo.00366.2004] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Several studies demonstrate an association between osteoporosis and arterial calcific disease, both of which being common in elderly women. Estradiol and raloxifene, a selective estrogen receptor modulator, prevent bone loss in postmenopausal women. Little is known regarding how these agents affect arterial calcification. The aim of this study was to determine whether or not 17beta-estradiol and raloxifene reduced vascular smooth muscle cell (VSMC) differentiation and expression of bone-associated proteins during phosphate-induced calcification in vitro. Aortic VSMC were cultured from adult, gonadally intact, and ovariectomized (OVX) female pigs. Calcifying medium was added, and cells were treated with solvent (control), 17beta-estradiol (E(2)), or raloxifene. Extent of calcification and phenotypic expression of bone-associated proteins [matrix gla protein (MGP), osteoprotegerin (OPG), and bone sialoprotein (BSP)] were examined at 3-day intervals over 2 wk. Calcium content increased in all groups but was greater in VSMC derived from intact compared with OVX animals. E(2) reduced calcification and preserved a contractile phenotype. Expression of OPG significantly decreased with time; this decrease was significantly greater in VSMC derived from OVX compared with gonadally intact pigs. E(2) and raloxifene preserved expression of OPG only in VSMC from intact pigs. Expression of MGP increased significantly with time and was not affected by E(2) or raloxifene treatments. E(2) treatment significantly inhibited synthesis of BSP in cells from both groups. In conclusion, E(2) slows differentiation of VSMC induced by excess phosphate. Effectiveness of raloxifene to preserve expression of bone cell-associated proteins depends on the hormonal status of the tissue donor.
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Affiliation(s)
- Ewa Rzewuska-Lech
- Department of Surgery, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA
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27
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Li GZ, Jiang W, Zhao J, Pan CS, Cao J, Tang CS, Chang L. Ghrelin blunted vascular calcification in vivo and in vitro in rats. ACTA ACUST UNITED AC 2005; 129:167-76. [PMID: 15927713 DOI: 10.1016/j.regpep.2005.02.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2004] [Accepted: 02/04/2005] [Indexed: 11/18/2022]
Abstract
Ghrelin is a new peptide with regulatory actions in growth hormone secretion in the anterior pituitary gland and in energy metabolism. Currently, ghrelin has potently protective effects in cardiovascular diseases. We used an in vivo model of rat vascular calcification induced by vitamin D3 and nicotine and one of cultured rat vascular smooth muscular cells (VSMCs) calcification induced by beta-glycerophosphate to study the possible mechanism in the regulatory action of ghrelin in vascular calcification. Calcification increased total Ca2+ content and 45Ca2+ deposition in aortas and VSMCs and alkaline phosphatase (ALP) activation in plasma, aortas and VSMCs. However, calcified aortas and VSMCs showed a significant decrease in osteopontin (OPN) mRNA expression and a marked reduction of ghrelin levels in plasma and its mRNA expression in aortas. The aortic calcification was significantly attenuated by subcutaneous administration of ghrelin 30 and 300 nmol kg(-1) day(-1) for 4 weeks, and the latter dosage was more potent than the former. Ghrelin treatment at the two dosages reduced the total aorta Ca2+ content by 24.4% and 28.1%, aortic 45Ca2+ deposition by 18.4% and 24.9%, plasma ALP activity by 36.6% and 76.7%, and aortic ALP activity by 10.3% and 47.6% (all P < 0.01 or 0.05), respectively. Ghrelin at 10(-8)-10(-6) mol/L attenuated the calcification in cultured VSMCs, with decreased total Ca2+ content, 45Ca2+ deposition and ALP activity and increased OPN mRNA expression, in a concentration-dependent manner. In addition, endothelin levels in plasma and aortas and its mRNA expression in aortas significantly increased with calcification, but ghrelin treatment significantly decreased endothelin levels and mRNA expression, with the high dosage being more potent than the lower dosage. These results indicate that local ghrelin in vascular was down-regulated during vascular calcification, whereas administration of ghrelin effectively attenuated vascular and VSMCs calcification.
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Affiliation(s)
- Gui-Zhong Li
- Institute of Cardiovascular Disease Research, First Hospital of Peking University, Beijing 100034, PR China
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28
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Bin G, Fen QY, Hua LX, Hong ZB, Zheng PY, Shu TC. Dysfunction of myocardial sarcoplasmic reticulum in rats with myocardial calcification. Life Sci 2005; 77:966-79. [PMID: 15964313 DOI: 10.1016/j.lfs.2004.12.037] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2004] [Accepted: 12/21/2004] [Indexed: 11/24/2022]
Abstract
We investigated the relationship between cardiac dysfunction and Ca2+ transport in the myocardial sarcoplasmic reticulum (SR) during the pathogenesis of cardiovascular calcification in rats. The possible mechanism of SR dysfunction was explored by detecting the alteration of the nitric oxide/nitric oxide synthase (NO/NOS) pathway in the SR. Using the vitamin D plus nicotine (VDN treatment for 2 week and 6 week) experimental model of cardiac calcification, cardiac function and sarcoplasmic reticulum function were measured. Inhibition of cardiac functions in vivo (peak rate of contraction and peak rate of relaxation, P < 0.05 or P < 0.01) were observed in all calcification groups, simultaneously, Ca2+ release and uptake in the SR as well as the Ca2+ release channel and Ca2+ pump activity were inhibited. Myocardial Ca2+ concentration and cardiac and SR dysfunction were inversely related (P < 0.05). The specific NO/NOS pathway (NO production, NOS activity and nNOS expression in the SR) was upregulated in the SR and associated with calcification (both 2- and 6 week VDN groups). These results indicate that cardiac dysfunction associated with myocardial calcification might be mediated by SR dysfunction, which may result from an impaired SR-specific NO/NOS pathway.
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Affiliation(s)
- Geng Bin
- Institute of Cardiovascular Research, Peking University First Hospital, Beijing, 100034, China
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29
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Abstract
PURPOSE OF REVIEW Accumulating evidence suggests that the high cardiovascular mortality observed in patients with end-stage renal disease is due in part to the deleterious effects of vascular calcification that develops over time on dialysis. This review focuses on recent cell biological and animal studies that have shed light on the mechanisms and regulators of vascular smooth muscle cell calcification in end-stage renal disease. RECENT FINDINGS Clinical studies demonstrate that high circulating levels of phosphate or calcium predict vascular calcification. Recent cell biological studies have provided novel insights into how vascular smooth muscle cells regulate calcification in response to such insults. Vascular smooth muscle cell damage and subsequent vesicle release from viable and dying cells create an environment permissive for the nucleation of basic calcium phosphate mineral. This, combined with osteogenic conversion of vascular smooth muscle cells and consequent loss of their normal inhibitory processes/pathways, results in calcification. Circulating factors such as fetuin-A, with the potential to impact on vessel wall calcification, have also been identified. Animal studies suggest that the 'uremic milieu' potentiates calcification and have clearly established a link between vascular calcification and bone metabolism. However, our understanding of the factors that contribute to vascular smooth muscle cell calcification in end-stage renal disease remains incomplete. SUMMARY Systematic studies are required that integrate epidemiological studies to identify risk factors with in-vitro experiments to investigate mechanisms leading to vascular smooth muscle cell calcification in response to these factors. Animal and clinical studies can subsequently be used to assess how modifying risk factors under the complex physiological conditions of end-stage renal disease impacts on vessel wall health.
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Pan CS, Qi YF, Wang SH, Zhao J, Bu DF, Li GZ, Tang CS. Alterations of adrenomedullin and its receptor system components in calcified vascular smooth muscle cells. ACTA ACUST UNITED AC 2004; 120:77-83. [PMID: 15177923 DOI: 10.1016/j.regpep.2004.02.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2003] [Revised: 02/18/2004] [Accepted: 02/25/2004] [Indexed: 11/17/2022]
Abstract
Vascular calcification is a common finding in many cardiovascular diseases. Paracrine/autocrine changes in calcified vessels, and the secreted factors participate in and play an important role in the progress of calcification. Adrenomedullin (ADM) is a potent vasodilator peptide secreted by vascular smooth muscle cells (VSMCs) and vascular endothelial cells. Recently, receptor activity-modifying proteins (RAMPs) have been shown to transport calcitonin receptor-like receptor (CRLR) to the cell surface to present either as CGRP receptor or ADM receptor. In this work, we explored the production of ADM, alterations and significance of ADM mRNA and its receptor system components--CRLR and RAMPs mRNA in calcified VSMCs. Our results showed that calcium content, 45Ca2+ uptake and alkaline phosphatases (ALPs) activity in calcified VSMCs were increased, respectively, compared with control VSMCs. Content of ADM in medium was increased by 99% (p < 0.01). Furthermore, it was found that the levels of ADM, CRLR, RAMP2 and RAMP3 mRNA in calcified cells were elevated, respectively, compared with that of control. The elevated levels of CRLR, RAMP2 and RAMP3 mRNA were significant correlation with ADM mRNA (r = 0.83, 0.92 and 0.93, respectively, all p's < 0.01) in calcified VSMCs. The results show that calcified VSMCs generate an increased amount of ADM, up-regulate gene expressions of ADM and its receptor system components--CRLR, RAMP2 and RAMP3, suggesting an important role of ADM and its receptor system in the regulation of vascular calcification.
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Affiliation(s)
- Chun Shui Pan
- Institute of Cardiovascular Diseases, Peking University First Hospital, Beijing 100034, China
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31
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Affiliation(s)
- Jürgen Floege
- Division of Nephrology and Immunology, University of Aachen, Aachen, Germany.
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33
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Speer MY, Giachelli CM. Regulation of cardiovascular calcification. Cardiovasc Pathol 2004; 13:63-70. [PMID: 15033154 DOI: 10.1016/s1054-8807(03)00130-3] [Citation(s) in RCA: 158] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2003] [Revised: 10/27/2003] [Accepted: 11/03/2003] [Indexed: 01/12/2023] Open
Abstract
Vascular calcification is highly correlated with cardiovascular disease (CVD) and is a significant predictor of cardiovascular events, especially in high risk patients such as the end stage renal disease (ESRD) population. Vascular calcification can lead to serious problems including valve stenosis, decreased vascular compliance, calciphylaxis, and even sudden death. However, the contribution of vascular calcification to progression of atherosclerosis is unknown and needs more study. Biochemical, histological, and genetic studies indicate that vascular calcification is actively regulated and involves both positive and negative modulators. Several nonmutually exclusive theories to account for vascular calcification based on current studies are discussed.
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Affiliation(s)
- Mei Y Speer
- Bioengineering Department, University of Washington, Box 351720, Okanogan Lane, Bagley Hall, Seattle, WA 98195, USA
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Kizu A, Shioi A, Jono S, Koyama H, Okuno Y, Nishizawa Y. Statins inhibit in vitro calcification of human vascular smooth muscle cells induced by inflammatory mediators. J Cell Biochem 2004; 93:1011-9. [PMID: 15389884 DOI: 10.1002/jcb.20207] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the progression of coronary artery and aortic valve calcification, the mechanism of action of these drugs to inhibit the calcification process remains unclear. In this study, we investigated the effect of statins such as cerivastatin and atorvastatin on vascular calcification by utilizing an in vitro model of inflammatory vascular calcification. Cerivastatin and atorvastatin dose-dependently inhibited in vitro calcification of human vascular smooth muscle cells (HVSMCs) induced by the following inflammatory mediators (IM): interferon-gamma, 1alpha,25-dihydroxyvitamin D3, tumor necrosis factor-alpha, and oncostatin M. These statins also depressed expression of alkaline phosphatase (ALP) in HVSMCs induced by these factors. Mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effect of cerivastatin on ALP expression in HVSMCs, while farnesylpyrophosphate showed no effect on the ALP activities inhibited by this drug, suggesting that inhibition of Rho and its downstream target, Rho kinase may mediate the inhibitory effect of cerivastatin. Cerivastatin prevented RhoA activation in HVSMCs induced by the IM. A specific inhibitor of Rho kinase (Y-27632) inhibited in vitro calcification and induction of ALP in HVSMCs. These findings provide a possible mechanism of statins to prevent the progression of calcification in inflammatory vascular diseases such as atherosclerosis and cardiac valvular calcification.
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MESH Headings
- Alkaline Phosphatase/metabolism
- Atorvastatin
- Calcinosis
- Dose-Response Relationship, Drug
- Heptanoic Acids/pharmacology
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
- Inflammation/metabolism
- Mevalonic Acid/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/immunology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/immunology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Polyisoprenyl Phosphates/metabolism
- Pyridines/pharmacology
- Pyrroles/pharmacology
- Sesquiterpenes
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Affiliation(s)
- Akane Kizu
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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35
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Wu SY, Zhang BH, Pan CS, Jiang HF, Pang YZ, Tang CS, Qi YF. Endothelin-1 is a potent regulator in vivo in vascular calcification and in vitro in calcification of vascular smooth muscle cells. Peptides 2003; 24:1149-56. [PMID: 14612185 DOI: 10.1016/j.peptides.2003.07.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We observed changes of endothelin content and endothelin mRNA in vivo in vascular calcification and in vitro in calcification of vascular smooth muscle cells to explore the role of endothelin in vascular calcification. Calcification model in vivo was induced by administration of Vitamin D(3) plus nicotine. Calcification of vascular smooth muscle cells (VSMCs) was induced by beta-glycerophosphate. Endothelin content was measured by using radioimmunoassay. Endothelin mRNA amount was determined by using competitive quantitative RT-PCR. The results showed that calcium content, 45Ca(2+) uptake and alkaline phosphatase (ALP) activity were increased in calcified VSMCs, compared with controls, but were decreased, compared with calcified VSMCs plus BQ123 group. The endothelin content in the medium and endothelin mRNA in VSMCs were elevated by 35 and 120% (P<0.05), respectively, compared with those normal VSMCs. Calcium content, 45Ca(2+) accumulation and ALP activity in calcified arteries increased by 5.0-, 1.4-, and 1.4-fold. The endothelin levels in plasma and aorta as well as the amount of endothelin mRNA in calcified aorta were increased by 102, 103, and 22%, respectively, compared with control group. However, calcium content, 45Ca(2+) uptake and ALP activity in VDN plus bosentan group was 33, 36.7, and 40.4% lower than those in VDN group. These results indicated an upregulated endothelin gene expression as well as an increased production of endothelin in calcified aorta and VSMCs with BQ123 and bosentan significantly reducing vascular calcification. This suggested that endothelin might be involved in pathogenesis of vascular calcification.
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Affiliation(s)
- Sheng Ying Wu
- Institute of Cardiovascular Disease, Peking University First Hospital, Beijing 100034, China
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36
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Huang Z, Li J, Jiang Z, Qi Y, Tang C, Du J. Effects of adrenomedullin, C-type natriuretic peptide, and parathyroid hormone-related peptide on calcification in cultured rat vascular smooth muscle cells. J Cardiovasc Pharmacol 2003; 42:89-97. [PMID: 12827032 DOI: 10.1097/00005344-200307000-00014] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
To clarify the regulating mechanism of vascular calcification, the investigators observed the effects of three vasoactive peptides, adrenomedullin (ADM), C-type natriuretic peptide (CNP), and parathyroid hormone-related peptide (PTHrP) on calcification in rat vascular smooth muscle cells (VSMCs). Beta-glycerophosphate stimulated growth and calcification in VSMCs. Adrenomedullin and CNP lowered beta-glycerophosphate-induced increase in VSMC growth. All three vasoactive peptides attenuated the increases of 45Ca accumulation, calcium content, and alkaline phosphatase activity in calcified VSMCs. As for comparing the inhibitory effects, the strongest was PTHrP. Both ADM and PTHrP increased cyclic adenosine monophosphate (cAMP) content in calcified VSMCs, but CNP upregulated cyclic guanosine monophosphate (cGMP) content. The PKA inhibitor PKAI completely reversed the inhibition of ADM on cell growth and all inhibitory effects of PTHrP on the parameters of calcification. The PKG inhibitor H8, however, strongly antagonized all the inhibitory effects of CNP on calcification. These data suggested that beta-glycerophosphate-induced calcification in VSMCs was inhibited by ADM, CNP, and PTHrP. Adrenomedullin and PTHrP inhibited VSMC calcification partially through the cAMP/PKA pathway, whereas CNP inhibited VSMC calcification through the cGMP/PKG pathway. This study could be of help in understanding the pathogenesis of vascular calcification, and providing new target for clinical treatment of cardiovascular diseases associated with vascular calcification.
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Affiliation(s)
- Zhiyu Huang
- Department of Physiology and Pathophysiology, Health Science Center, Peking University, Beijing, PR China
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37
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Qi YF, Wang SH, Zhang BH, Bu DF, Shu TC, Du JB. Changes in amount of ADM mRNA and RAMP2 mRNA in calcified vascular smooth muscle cells. Peptides 2003; 24:287-94. [PMID: 12668214 DOI: 10.1016/s0196-9781(03)00036-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
This work was aimed to explore the changes and significance of adrenomedullin (ADM) mRNA and receptor activity modifying protein 2 (RAMP2) mRNA in calcified vascular smooth muscle cells (VSMCs). Calcification of cultured rat VSMCs was produced by incubation with beta-glycerophosphate. Content of ADM released by VSMCs was measured by radioimmunoassay (RIA). The amount of ADM mRNA and RAMP2 mRNA was determined by competitive quantitative RT-PCR. The intracellular calcium content, alkaline phosphatases activity and cellular (45)Ca(2+)-uptake were determined. The results showed that the content of calcium, (45)Ca(2+)-uptake and alkaline phosphatases activity in calcified VSMCs were increased by 118%, 174% and seven-fold (all P<0.01), respectively, compared with control VSMCs. Content of ADM in medium was increased by 99% (P<0.01). Furthermore, it was found that the amount of ADM mRNA and RAMP2 mRNA in calcified cells was elevated by 78 and 56% (all P<0.05), respectively, compared with control. The elevated levels of RAMP2 mRNA were in positive correlation with ADM mRNA (r=0.76, P<0.05) in calcified VSMCs. In conclusion, calcified VSMCs generated an increased amount of ADM, and up-regulated gene expressions of ADM and RAMP2.
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MESH Headings
- Adrenomedullin
- Alkaline Phosphatase/metabolism
- Animals
- Calcium/metabolism
- Calcium Chloride/pharmacology
- Cells, Cultured
- Glycerophosphates/chemistry
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins/genetics
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Peptides/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Radioimmunoassay
- Rats
- Rats, Wistar
- Receptor Activity-Modifying Protein 2
- Receptor Activity-Modifying Proteins
- Reverse Transcriptase Polymerase Chain Reaction
- Up-Regulation/drug effects
- Up-Regulation/genetics
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Affiliation(s)
- Yong Fen Qi
- Institute of Cardiovascular Diseases, Peking University First Hospital, 100034, PR, Beijing, China
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38
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Zhang B, Tang C, Du J. Changes of heme oxygenase-carbon monoxide system in vascular calcification in rats. Life Sci 2003; 72:1027-37. [PMID: 12495781 DOI: 10.1016/s0024-3205(02)02352-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of the present study was to investigate the change in heme oxygenase (HO)-carbon monoxide (CO)-cyclic guanosine monophosphate (cGMP) pathway in vascular calcification. Vascular calcification model was established in rats by using vitamin D(3) and nicotine. Vascular calcium content, alkaline phosphatase (ALP) activity, HO activity, HbCO formation and content of cGMP in vessels were measured. Immunochemistry (IH) for HO 1 expression and in situ hybridization (ISH) for HO 1 mRNA were observed. Compared to those of control rats, the aortic calcium content and vascular ALP activity in rats of the calcified group (VDN group) were obviously increased, but HO 1 activity, CO concentration and cGMP content in vessels of rats in VDN group were markedly decreased. Expressions of HO-1 protein and mRNA were significantly decreased compared to control rats. Vascular calcification might induce a down regulation in vascular HO-CO-cGMP pathway.
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Affiliation(s)
- Baohong Zhang
- Department of Pediatrics, First Hospital, Peking University, Beijing 100034, PR China
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39
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Sweatt A, Sane DC, Hutson SM, Wallin R. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost 2003; 1:178-85. [PMID: 12871556 DOI: 10.1046/j.1538-7836.2003.00023.x] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The vitamin K-dependent protein, matrix Gla protein (MGP) is a binding protein for bone morphogenetic protein-2 (BMP-2). Here we present additional evidence that the Ca2+-induced conformer of the vitamin K-dependent Gla region in MGP is involved in BMP-2 binding. Recombinant BMP-2 binds to the Gla-containing region of MGP in the presence of Ca2+. Immunohistochemistry showed that calcified lesions in the aortic wall of aging rats contained elevated concentrations of MGP that was poorly gamma-carboxylated and did not bind BMP-2. In contrast, we were able to identify glandular structures in the mucosa of the rat nasal septum that gave bright fluorescent signals with both antigens; confocal microscopy confirmed their colocalization. These results demonstrate that the BMP-2/MGP complex exists in vivo, consistent with a role for MGP as a BMP-2 inhibitor. Age-related arterial calcification may be a consequence of under-gamma-carboxylation of MGP, allowing unopposed BMP-2 activity.
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Affiliation(s)
- A Sweatt
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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40
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Davis MDP, Pittelkow MR, Lindor NM, Lundstrom CE, Fitzpatrick LA. Progressive extensive osteoma cutis associated with dysmorphic features: a new syndrome? Case report and review of the literature. Br J Dermatol 2002; 146:1075-80. [PMID: 12072082 DOI: 10.1046/j.1365-2133.2002.04674.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Osteoma cutis, also called cutaneous ossification, refers to the rare occurrence of bone in the skin. It may be primary, occurring in normal skin, or secondary, occurring in disrupted skin tissue. A 42-year-old white woman presented with long-standing progressive primary osteoma cutis involving her head and neck, trunk and extremities. She had craniofacial dysmorphism with mid-face hypoplasia, including saddle nose deformity, mild to moderate generalized joint hypermobility, extensive paravertebral ossification, and disc space calcification. The differential diagnosis for this entity is presented. This phenotype may be a previously undescribed syndrome.
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Affiliation(s)
- M D P Davis
- Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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41
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Abstract
BACKGROUND Composed of endocardial endothelial, valvular interstitial, cardiac muscle, and smooth muscle cells (SMC), heart valves are prone to various pathologic conditions the morphology of which has been well described. The morphology of diseased valves suggest that the "response to injury" process occurs in these valves, and is associated with an accumulation of interstitial cells and matrix, valvular inflammation and calcification, conditions that lead to dysfunction. The purpose of this study is to describe the current knowledge of the regulation of the valvular "response to injury" process, since we feel that this paradigm is essential to understanding valve disease. METHODS The pertinent literature relating to the cell and molecular biology of valvular repair, and specifically interstitial cell function in valve repair, is reviewed. RESULTS The cell and molecular biology of valve interstitial cells are poorly understood. Molecules regulating some of the aspects of the "response to injury" process have been studied, however, the signal transduction pathways, gene activation, and interactions of bioactive molecules with each other, with cells, and with the matrix have not been characterized. Initial studies identify the cell and molecular biology of interstitial cells to be an important area of research. Agents that have been studied include nitric oxide (NO) and FGF-2 and several matrix-related proteins including osteopontin. The present review suggests several directions for future study and a working model of valvular repair is presented. DISCUSSION The regulation of the "response to injury" process in the human heart valve is still largely unknown. The cell and molecular events and processes that occur in heart valve function and repair remain poorly understood. These events and processes are vital to our understanding of the pathobiology of heart valve disease, and to the successful design of tissue engineered replacement valves.
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Affiliation(s)
- Adam D Durbin
- Toronto General Research Institute, Toronto, Ontario, Canada
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42
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Abstract
Vascular calcification has been clearly defined as a risk factor for cardiovascular mortality in the general population and is highly prevalent in end-stage renal disease (ESRD), where it is associated with a number of markers of increased mortality such as left ventricular hypertrophy. The pattern of calcification in ESRD is characterized by mineral deposition in the tunica media, in contrast to non-ESRD populations, where calcification of atheromatous plaque predominates. This difference may have important clinical implications. The pathophysiological mechanisms underlying both types of vascular calcification remain to be clarified; however, current evidence suggests that they are active processes rather than passive mineral precipitation, and the presence in the vasculature of cells expressing an osteoblastic phenotype may be of central importance. In ESRD, the presence of secondary and tertiary hyperparathyroidism, disordered calcium and phosphate homeostasis, and the use of vitamin D- and calcium-based treatments in its therapy may all contribute to vascular calcification. These issues and the impact on other current and future therapies have great importance for clinical nephrology, and a better understanding of vascular calcification through a focused research effort is essential.
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Affiliation(s)
- M R Davies
- Renal Division, Barnes-Jewish Hospital, St. Louis, Missouri, USA.
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43
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Wallin R, Wajih N, Greenwood GT, Sane DC. Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev 2001; 21:274-301. [PMID: 11410932 DOI: 10.1002/med.1010] [Citation(s) in RCA: 168] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The causes of arterial calcification are beginning to be elucidated. Macrophages, mast cells, and smooth muscle cells are the primary cells implicated in this process. The roles of a variety of bone-related proteins including bone morphogenetic protein-2 (BMP-2), matrix Gla protein (MGP), osteoprotegerin (OPG), osteopontin, and osteonectin in regulating arterial calcification are reviewed. Animals lacking MGP, OPG, smad6, carbonic anhydrase isoenzyme II, fibrillin-1, and klotho gene product develop varying extents of arterial calcification. Hyperlipidemia, vitamin D, nicotine, and warfarin, alone or in various combinations, produce arterial calcification in animal models. MGP has recently been discovered to be an inhibitor of bone morphogenetic protein-2, the principal osteogenic growth factor. Many of the forces that induce arterial calcification may act by disrupting the essential post-translational modification of MGP, allowing BMP-2 to induce mineralization. MGP requires gamma-carboxylation before it is functional, and this process uses vitamin K as an essential cofactor. Vitamin K deficiency, drugs that act as vitamin K antagonists, and oxidant stress are forces that could prevent the formation of GLA residues on MGP. The potential role of arterial apoptosis in calcification is discussed. Potential therapeutic options to limit the rate of arterial calcification are summarized.
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Affiliation(s)
- R Wallin
- Section of Rheumatology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
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44
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Jian B, Jones PL, Li Q, Mohler ER, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. THE AMERICAN JOURNAL OF PATHOLOGY 2001; 159:321-7. [PMID: 11438479 PMCID: PMC1850407 DOI: 10.1016/s0002-9440(10)61698-7] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
We previously showed that the expression of tenascin (TN-C), an extracellular matrix glycoprotein found in developing bone and atherosclerotic plaque, and matrix metalloproteinase-2 (MMP-2) are coordinated and interdependent in cultured vascular smooth muscle cells. In this study, we hypothesized that TN-C and MMP-2 are mechanistically involved in the pathobiology of calcific aortic stenosis. Human calcific aortic stenosis cusps demonstrated immunohistochemically prominent deposition of TN-C, MMP-2, and alkaline phosphatase activity, as well as MMP-2 gelatinolytic activity. Although far lesser amounts of TN-C were noted in several of the grossly non-calcified valve cusps, MMP-2 and AP were never detected. Further, when aortic valve interstitial cells (both sheep and human) were cultivated on collagen supplemented with TN-C, both MMP-2 mRNA expression and MMP-2 gelatinolytic activity (both pro and active forms), were up-regulated compared to control. These observations support the view that accumulation of first TN-C and then MMP-2 are associated with progression of calcification. The residual presence of these proteins in severe calcifications is indicative of their involvement in the pathogenesis.
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Affiliation(s)
- B Jian
- Cardiology Research Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA
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45
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Hodgin JB, Krege JH, Reddick RL, Korach KS, Smithies O, Maeda N. Estrogen receptor alpha is a major mediator of 17beta-estradiol's atheroprotective effects on lesion size in Apoe-/- mice. J Clin Invest 2001; 107:333-40. [PMID: 11160157 PMCID: PMC199197 DOI: 10.1172/jci11320] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The inhibitory effects of estrogen (17beta-estradiol) on atherosclerosis have been well documented in numerous animal models, and epidemiological evidence supports this protective effect in humans. The detailed mechanisms for this protection are not understood, but most are thought to be mediated through estrogen receptors (ERs), of which two are known (ERalpha and ERbeta). To investigate the role of ERalpha in the atheroprotective effect of 17beta-estradiol (E2), we ovariectomized female mice that lack apoE (AAee) or lack both apoE and ERalpha (alphaalphaee), and treated half of them with E2 for three months. E2 treatment of ovariectomized AAee females dramatically reduced the size of the lesions as well as their histological complexity. Plasma cholesterol was significantly reduced in this group, although the observed extent of protection by E2 was greater than could be explained solely by the change in lipid levels. In contrast, E2 treatment of ovariectomized alphaalphaee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with alphaalphaee mice without E2, demonstrating that ERalpha is a major mediator of the atheroprotective effect of E2. Nevertheless, E2 treatment significantly reduced the complexity of plaques in the alphaalphaee females, although not to the same degree as in AAee females, suggesting the existence of ERalpha-independent atheroprotective effects of E2.
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Affiliation(s)
- J B Hodgin
- Department of Pathology and Laboratory Medicine, University of North Carolina, 703 Brinkhous-Bullitt Building, Chapel Hill, North Carolina 27599-7525, USA
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46
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Rostand SG. Coronary heart disease in chronic renal insufficiency: some management considerations. J Am Soc Nephrol 2000; 11:1948-1956. [PMID: 11004228 DOI: 10.1681/asn.v11101948] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Affiliation(s)
- Stephen G Rostand
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
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47
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Graves DC, Yablonka-Reuveni Z. Vascular smooth muscle cells spontaneously adopt a skeletal muscle phenotype: a unique Myf5(-)/MyoD(+) myogenic program. J Histochem Cytochem 2000; 48:1173-93. [PMID: 10950875 DOI: 10.1177/002215540004800902] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Smooth and skeletal muscle tissues are composed of distinct cell types that express related but distinct isoforms of the structural genes used for contraction. These two muscle cell types are also believed to have distinct embryological origins. Nevertheless, the phenomenon of a phenotypic switch from smooth to skeletal muscle has been demonstrated in several in vivo studies. This switch has been minimally analyzed at the cellular level, and the mechanism driving it is unknown. We used immunofluorescence and RT-PCR to demonstrate the expression of the skeletal muscle-specific regulatory genes MyoD and myogenin, and of several skeletal muscle-specific structural genes in cultures of the established rat smooth muscle cell lines PAC1, A10, and A7r5. The skeletal muscle regulatory gene Myf5 was not detected in these three cell lines. We further isolated clonal sublines from PAC1 cultures that homogeneously express smooth muscle characteristics at low density and undergo a coordinated increase in skeletal muscle-specific gene expression at high density. In some of these PAC1 sublines, this process culminates in the high-frequency formation of myotubes. As in the PAC1 parental line, Myf5 was not expressed in the PAC1 sublines. We show that the PAC1 sublines that undergo a more robust transition into the skeletal muscle phenotype also express significantly higher levels of the insulin-like growth factor (IGF1 and IGF2) genes and of FGF receptor 4 (FGFR4) gene. Our results suggest that MyoD expression in itself is not a sufficient condition to promote a coordinated program of skeletal myogenesis in the smooth muscle cells. Insulin administered at a high concentration to PAC1 cell populations with a poor capacity to undergo skeletal muscle differentiation enhances the number of cells displaying the skeletal muscle differentiated phenotype. The findings raise the possibility that the IGF signaling system is involved in the phenotypic switch from smooth to skeletal muscle. The gene expression program described here can now be used to investigate the mechanisms that may underlie the propensity of certain smooth muscle cells to adopt a skeletal muscle identity.(J Histochem Cytochem 48:1173-1193, 2000)
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Affiliation(s)
- D C Graves
- Department of Biological Structure, School of Medicine, University of Washington, Seattle, Washington 98195, USA
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48
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Chanda S, Robinette CL, Couse JF, Smart RC. 17beta-estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-alpha pathway. Am J Physiol Endocrinol Metab 2000; 278:E202-10. [PMID: 10662703 DOI: 10.1152/ajpendo.2000.278.2.e202] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Estradiol (E(2)) applied topically twice weekly to mouse skin at doses as low as 1 nmol inhibited hair growth by blocking the transition of the hair follicle from the resting phase (telogen) to the growth phase (anagen). In contrast, application of </=10 nmol of other steroids produced limited inhibition. Topical treatment with the estrogen receptor (ER) antagonist ICI-182780 reversed the effects of E(2), and when applied alone, ICI-182780 caused a telogen-to-anagen transition. Both E(2) and ICI-182780 were highly effective at their site of application but not at distant sites, indicating the direct rather than secondary systemic nature of their effects. Western analysis detected a 65-kDa ER-alpha immunoreactive dermal protein, and Northern analysis revealed the presence of a 6.7-kb ER-alpha mRNA. A ribonuclease protection assay confirmed the presence of ER-alpha transcripts but failed to detect ER-beta transcripts. These findings implicate a skin-specific ER-alpha pathway in the regulation of the hair follicle cycle.
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Affiliation(s)
- S Chanda
- Molecular and Cellular Toxicology, Department of Toxicology, Physiological Sciences and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27695, USA
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49
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Abstract
Calcification is a component of vascular disease that usually occurs in concert with atheroma formation but through distinct pathophysiological processes. Vessel wall osteoprogenitor cells known as calcifying vascular cells can form bone matrix proteins and calcified nodules, analogous to osteoblastic differentiation in bone. These cells have been isolated from the tunica media of bovine and human arteries, and both in-vitro tissue culture models and mouse models of vascular calcification have been established. Studies of the effects of diabetes mellitus, hyperlipidemia, estrogens and glucocorticoids on calcifying vascular cell function provide insight into the relationship between common human disease states and vascular calcification.
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Affiliation(s)
- M G Jakoby
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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50
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Bianco P, Cossu G. Uno, nessuno e centomila: searching for the identity of mesodermal progenitors. Exp Cell Res 1999; 251:257-63. [PMID: 10471311 DOI: 10.1006/excr.1999.4592] [Citation(s) in RCA: 95] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- P Bianco
- Dipartimento di Medicina Sperimentale, Università de L'Aquila, L'Aquila, Italy.
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