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      Correlation between genetic polymorphism of matrix metalloproteinase-9 in patients with coronary artery disease and cardiac remodeling

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          Abstract

          Objective:

          To explore the correlation between genetic polymorphism of matrix metalloproteinase-9 (MMP-9) in patients with coronary artery disease (CAD) and cardiac remodeling.

          Methods:

          A total of 272 subjects who received coronary angiography in our hospital from July 2008 to September 2013 were selected, including 172 CAD patients (CAD group) and another 100 ones (control group). Both groups were subjected to MMP-9 and ultrasonic detections to determine vascular remodeling and atherosclerotic plaques. C1562G polymorphism of MMP-9 gene was detected, and correlation with vascular remodeling and atherosclerotic plaque was analyzed.

          Results:

          Serum MMP-9 level of CAD group (330.87±50.39 ng/ml) was significantly higher than that of control group (134.87±34.02 ng/ml) (P<0.05). Compared with control group, CAD group had significantly higher intima-media thickness, and significantly lower systolic peak velocity, mean systolic velocity and end-diastolic velocity (P<0.05). Total area of stenotic blood vessels was 67.34±22.98 mm 2, while that of control blood vessels was 64.00±20.83 mm 2. G/G, G/C and C/C genotype frequencies of MMP-9 differed significantly in the two groups (P<0.05). G and C allele frequencies of CAD group (70.9% and 29.1%) were significantly different from those of control group (50.0% and 50.0%) (P<0.05). G/G, G/C and C/C genotypes were manifested as lipid-rich, fibrous and calcified or ulcerated plaques respectively. Total area of stenotic blood vessels of G/G genotype significantly exceeded those of G/C and C/C genotypes (P<0.05), whereas the latter two had no significant differences.

          Conclusion:

          CAD promoted 1562C-G transformation of MMP-9 gene into genetic polymorphism, thus facilitating arterial remodeling and increasing unstable atherosclerotic plaques.

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          Most cited references21

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          MicroRNA-21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs.

          Coronary atherosclerotic unstable plaque is one of the leading causes of cardiovascular death. Macrophage-derived matrix metalloproteinase (MMP) 9 is considered for degrading extracellular matrix and collagen, thereby thinning the fibrous cap in plaques. miR-21 is implicated to play an important role in the progression of atherosclerosis. Nevertheless, miR-21 as the biomarker for coronary atherosclerotic unstable plaque remains unknown. We aimed to investigate the prediction role of miR-21 for unstable plaque by pathway study of miR-21 on MMPs and its inhibitor RECK in macrophages. Expression of miR-21 in macrophages and serum miR-21 as well as MMP-9 was measured in patients with coronary non-calcified plaque, calcified plaque and controls. In vitro experiment was done in human macrophages by over-expressing miR-21 or down-regulating RECK. The regulation of RECK and MMP-9 by miR-21 was evaluated by western blotting and siRNA strategy. Patients with non-calcified coronary artery lesions had significantly higher miR-21 in macrophages and lower miR-21 serum levels compared to the control and calcified plaque patients. At the same time, the serum levels of MMP-9 were significantly elevated in non-calcified patients. Experiments in vitro indicated that over-expressing miR-21 could induce the expression and secretion of pro-MMP-9 and active-MMP-9 in human macrophages via targeting gene RECK, and knocking down RECK expression by specific siRNA can resemble that of miR-21 over-expression. miR-21 might be a biomarker for plaque instability by suppressing target gene RECK to promote the expression and secretion of MMP-9 in macrophages. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Exploring the Role of Paraoxonases in the Pathogenesis of Coronary Artery Disease: A Systematic Review

            Paraoxonases (PON) are three enzymes (PON1, PON2 and PON3) that play a role in the organism’s antioxidant system; alterations in which are associated with diseases involving oxidative stress. In this review, we summarize the evidence of PON related to the pathogenesis of coronary artery disease (CAD) and atherosclerosis. We searched three electronic databases (PubMed, Scopus and Cochrane Database) with no date limit. All of the articles selected investigated PON enzymatic activity and/or PON gene polymorphisms. The selection focused on PON in relation to atherosclerosis, CAD and myocardial infarction. The exclusion criteria were a sample size <100 patients, non-human studies, editorials and systematic reviews without restrictions on the country of origin. With these criteria, we identified thirty-five prospective studies published between 1986 and 2014 with a total of 28,164 participants. The relationship between PON gene polymorphisms and CAD was not conclusive, but most studies support the concept that alterations in PON1 enzymatic activity levels do influence atheroma formation. Conversely, relationships between PON2 and PON3 vs. CAD have not been extensively investigated. Our review of the current data concludes that the bases of paraoxonases involvement in atherosclerosis are poorly understood and that this issue requires future comprehensive, multi-centered studies.
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              Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice.

              Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE(-/-)) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy. Copyright © 2014 Elsevier GmbH. All rights reserved.
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                Author and article information

                Journal
                Pak J Med Sci
                PJMS
                Pakistan Journal of Medical Sciences
                Professional Medical Publications (Pakistan )
                1682-024X
                1681-715X
                2015
                : 31
                : 3
                : 648-653
                Affiliations
                [1 ]Qibin Yu, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Peking 100037, China
                [2 ]Hanmei Li, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Peking 100037, China
                [3 ]Linlin Li, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Peking 100037, China
                [4 ]Shaoye Wang, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Peking 100037, China
                [5 ]Yongbo Wu, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Peking 100037, China
                Author notes
                Correspondence: Yongbo Wu, Department of Cardiosurgery, Fuwai Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Peking 100037, China. E-mail: wuybdc@ 123456yeah.net
                Article
                PJMS-31-648
                10.12669/pjms.313.7229
                4485288
                40894383-17ae-4c42-ae53-bfe3688b4b99
                Copyright: © Pakistan Journal of Medical Sciences

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 January 2015
                : 08 March 2015
                : 15 March 2015
                Categories
                Original Article

                coronary artery disease,matrix metalloproteinase-9,genetic polymorphism,cardiac remodeling

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