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      Deep Sea Water Prevents Balloon Angioplasty-Induced Hyperplasia through MMP-2: An In Vitro and In Vivo Study

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          Abstract

          Major facts about the development of restenosis include vascular smooth muscle cells (VSMCs) proliferation and migration. A previous study showed that in vitro treatment with magnesium chloride has the potential to affect the proliferation and migration of VSMCs. Magnesium is the major element in deep sea water (DSW) and is a biologically active mineral. It is unclear whether DSW intake can prevent abnormal proliferation and migration of VSMCs as well as balloon angioplasty-induced neointimal hyperplasia. Thus, we attempted to evaluate the anti-restenotic effects of DSW and its possible molecular mechanisms. Several concentrations of DSW, based on the dietary recommendations (RDA) for magnesium, were applied to a model of balloon angioplasty in SD rats. The results showed that DSW intake markedly increased magnesium content within the vascular wall and reduced the development of neointimal hyperplasia. The immunohistochemical analysis also showed that the expression of proteins associated with cell proliferation and migration were decreased in the balloon angioplasty groups with DSW supplement. Furthermore, in vitro treatment with DSW has a dose-dependent inhibitory effect on serum-stimulated proliferation and migration of VSMCs, whose effects might be mediated by modulation of mitogen-activated protein kinase (MAPK) signaling and of the activity of matrix metalloproteinase-2 (MMP-2). Our study suggested that DSW intake can help prevent neointimal hyperplasia (or restenosis), whose effects may be partially regulated by magnesium and other minerals.

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          MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets.

          Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.
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            The role of magnesium in hypertension and cardiovascular disease.

            Magnesium intake of 500 mg/d to 1000 mg/d may reduce blood pressure (BP) as much as 5.6/2.8 mm Hg. However, clinical studies have a wide range of BP reduction, with some showing no change in BP. The combination of increased intake of magnesium and potassium coupled with reduced sodium intake is more effective in reducing BP than single mineral intake and is often as effective as one antihypertensive drug in treating hypertension. Reducing intracellular sodium and calcium while increasing intracellular magnesium and potassium improves BP response. Magnesium also increases the effectiveness of all antihypertensive drug classes. It remains to be conclusively proven that cardiovascular disease such as coronary heart disease, ischemic stroke, and cardiac arrhythmias can be prevented or treated with magnesium intake. Preliminary evidence suggests that insulin sensitivity, hyperglycemia, diabetes mellitus, left ventricular hypertrophy, and dyslipidemia may be improved with increased magnesium intake. Various genetic defects in magnesium transport are associated with hypertension and possibly with cardiovascular disease. Oral magnesium acts as a natural calcium channel blocker, increases nitric oxide, improves endothelial dysfunction, and induces direct and indirect vasodilation. © 2011 Wiley Periodicals, Inc.
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              Magnesium supplementation helps to improve carotid intima media thickness in patients on hemodialysis.

              The atherosclerotic process progresses more dynamically in hemodialysis (HD) patients than in the general population. In HD patients, lower magnesium levels were reported to be associated with increased atherosclerosis of the common carotid artery. We tested the hypotheses that magnesium supplementation helps to improve carotid intima media thickness (IMT) in HD patients. A total of 47 patients on HD were included in the study. Patients were randomly divided into two groups: group A (Mg group), in which patients were given magnesium citrate orally at a dosage of 610 mg every other day for 2 months and group B (control group), in which patients received only calcium acetate therapy as a phosphate binder. At baseline and 2 months later, all patients underwent a carotid artery ultrasound scan to measure carotid IMT. At the end of 2 months, mean serum calcium, phosphorus, and calcium x phosphorus product were not changed in both groups. As expected, mean serum Mg level significantly increased in the Mg group at the end of 2 months. In addition, serum parathyroid hormone (PTH) level significantly decreased in the Mg group at the end of 2 months (P = 0.003). Baseline carotid IMT was similar between the groups. Bilateral carotid IMT was significantly improved in patients treated with magnesium citrate compared to initial values (P = 0.001 for left, P = 0.002 for right). Based on the present data, magnesium may play an important protective role in the progression of atherosclerosis in patients on dialysis. Further studies are needed to assess more accurately the role of magnesium in atherosclerotic regression in dialysis patients.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                13 May 2014
                : 9
                : 5
                : e96927
                Affiliations
                [1 ]School of Pharmacy, China Medical University, Taichung, Taiwan
                [2 ]College of Pharmacy, Taipei Medical University, Taipei, Taiwan
                [3 ]Department of Public Health, China Medical University, Taichung, Taiwan
                [4 ]School of Nursing, China Medical University, Taichung, Taiwan
                [5 ]Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
                University of Iowa, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PCL CHP CHW. Performed the experiments: PCL CCW CHP. Analyzed the data: PCL MJS WFM CHW. Wrote the paper: PCL.

                Article
                PONE-D-13-51970
                10.1371/journal.pone.0096927
                4019650
                24824358
                4cea738e-dfbf-404b-843f-01cb895caa4a
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 December 2013
                : 13 April 2014
                Page count
                Pages: 9
                Funding
                This research was supported by a grant from China Medical University (CMU-10142624). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Agriculture
                Animal Management
                Anatomy
                Biological Tissue
                Muscle Tissue
                Muscle Cells
                Biochemistry
                Cell Biology
                Cellular Types
                Molecular Cell Biology
                Marine Biology
                Organisms
                Animals
                Vertebrates
                Mammals
                Rodents
                Rats
                Veterinary Science
                Medicine and Health Sciences
                Research and Analysis Methods
                Animal Studies
                Animal Models of Disease
                Model Organisms
                Animal Models
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                Clinical Research Design

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