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      The association between BMP4 gene polymorphism and its serum level with the incidence of LVH in hypertensive patients

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          Abstract

          Background

          Bone morphogenic proteins 4 (BMP4) is associated with cardiac remodeling under different conditions. However, the role of BMP4 and its gene polymorphism in the incidence of left ventricular hypertrophy (LVH) in hypertensive patients remains unknown.

          Methods

          A total of 1265 patients diagnosed with essential hypertension (EH) were recruited. Patients were assigned to LVH+ (n = 420) and LVH- (n = 845) groups. serum BMP4 level was measured and two single nucleotide polymorphism (SNPs) polymorphisms, 6007C > T and -5826G > A of BMP4 gene were genotyped. We also inhibited the BMP4 by small interfering RNA (siRNA). The effect of BMP4 on the hypertrophic response in Human Cardiomyocytes AC16 cells was studied.

          Results

          We found that the 6007C > T polymorphism of the BMP4 gene and the serum BMP4 level were significantly associated with the risk to develop LVH. With TT as reference, multivariate logistic regression analysis showed the 6007CC genotype carriers had a higher susceptibility to LVH incidence (adjusted OR = 2.65, 95% CI: 1.63-4.31, adjusted P < 0.001). Our in vitro study shows that the BMP4 inhibition in cardiomyocyte by si-RNA technique significantly decreased the Ang II induced cardiomyocyte size and protein content per cell, indicating the importance of BMP4 in the cardiomyocyte hypertrophy.

          Conclusion

          Collectively, our data suggest that both the 6007C > T of the BMP4 gene and the serum BMP4 level may be used as potential marker for LVH incidence among the EH patients.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-014-0368-x) contains supplementary material, which is available to authorized users.

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          Most cited references 37

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          Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

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            Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response.

            Atherosclerosis is now viewed as an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions, including oscillatory shear stress (OS), in branched arteries. In contrast, the arterial regions exposed to laminar shear (LS) are relatively lesion-free. The mechanisms underlying the opposite effects of OS and LS on the inflammatory and atherogenic processes are not clearly understood. Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4 protein expression, whereas LS decreased it. In addition, we found BMP4 expression only in the selective patches of endothelial cells overlying foam cell lesions in human coronary arteries. The same endothelial patches also expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1) protein compared with those of non-diseased areas. Functionally, we show that OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a NFkappaB-dependent mechanism. We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas.
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              RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway.

              Vascular calcification commonly associated with several pathologies and it has been suggested to be similar to bone mineralization. The axis RANKL-OPG (receptor activator of nuclear factor kappaB ligand-osteoprotegerin) finely controls bone turnover. RANKL has been suggested to increase vascular calcification, but direct evidence is missing. Thus, in the present work, we assess the effect of RANKL in vascular smooth muscle cell (VSMC) calcification. VSMCs incubated with RANKL showed a dose-dependent increase in calcification, which was abolished by coincubation with OPG. To test whether the effect was mediated by signaling to its receptor, knockdown of RANK was accomplished by short hairpin (sh)RNA. Indeed, cells lacking RANK showed no increases in vascular calcification when incubated with RANKL. To further elucidate the mechanism by which RANK activation increases calcification, we blocked both nuclear factor (NF)-kappaB activation pathways. Only IKKalpha inactivation inhibited calcification, pointing to an involvement of the alternative NF-kappaB activation pathway. Furthermore, RANKL addition increased bone morphogenetic protein (BMP)4 expression in VSMCs, and that increase disappeared in cells lacking RANK or IKKalpha. The increase in calcification was also blunted by Noggin, pointing to a mediation of BMP4 in the calcification induced by RANKL. Furthermore, in an in vivo model, the increase in vascular calcium content was parallel to an increase in RANKL and BMP4 expression, which was localized in calcified areas. However, blood levels of the ratio RANKL/OPG did not change. We conclude that RANKL increases vascular smooth muscle cell calcification by binding to RANK and increasing BMP4 production through activation of the alternative NF-kappaB pathway.
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                Author and article information

                Affiliations
                [ ]Department of cardiovascular diseases, Jiangyin Hospital of traditional Chinese medicine affiliated Nanjing University of Chinese Medicine, Jiangyin, 214400 Jiangsu China
                [ ]Department of cardiovascular diseases, Wuxi Hospital of traditional Chinese medicine, Jiangyin, 214400 Jiangsu China
                [ ]Department of cardiovascular diseases, The People’s Hospital of Jiangyin, Jiangyin, 214400 Jiangsu China
                [ ]Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai, 214400 PR China
                Contributors
                sh_gugl@126.com
                ligongzi12@tom.com
                dr_sun1@tom.com
                dr_sas@tom.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                16 January 2015
                16 January 2015
                2015
                : 13
                368
                10.1186/s12967-014-0368-x
                4324029
                25591903
                © Gu et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                © The Author(s) 2015

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