期刊论文详细信息
Journal of Translational Medicine
The association between BMP4 gene polymorphism and its serum level with the incidence of LVH in hypertensive patients
XL Xu2  RL Zeng3  QY Yang4  GL Gu1 
[1] Department of cardiovascular diseases, Jiangyin Hospital of traditional Chinese medicine affiliated Nanjing University of Chinese Medicine, Jiangyin 214400, Jiangsu, China;Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 214400, PR China;Department of cardiovascular diseases, The People’s Hospital of Jiangyin, Jiangyin 214400, Jiangsu, China;Department of cardiovascular diseases, Wuxi Hospital of traditional Chinese medicine, Jiangyin 214400, Jiangsu, China
关键词: Small interfering RNA;    Left ventricular hypertrophy;    Essential hypertension;    Bone morphogenic proteins 4;   
Others  :  1146197
DOI  :  10.1186/s12967-014-0368-x
 received in 2014-09-10, accepted in 2014-12-17,  发布年份 2015
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【 摘 要 】

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.

【 授权许可】

   
2015 Gu et al.; licensee BioMed Central.

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【 参考文献 】
  • [1]Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, et al.: Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population. J Hypertens 2008, 26:1602-1611.
  • [2]Petrovic D, Stojimirovic B: Left ventricular hypertrophy in patients treated with regular hemodialyses. Med Pregl 2008, 61:369-374.
  • [3]Kaplinsky E: Significance of left ventricular hypertrophy in cardiovascular morbidity and mortality. Cardiovasc Drugs Ther 1994, 8(Suppl 3):549-556.
  • [4]Tovillas-Moran FJ, Vilaplana-Cosculluela M, Zabaleta-del-Olmo E, Dalfo-Baque A, Galceran JM, et al.: Cardiovascular morbidity and mortality and electrocardiographic criteria of left ventricular hypertrophy in hypertensive patients treated in primary care. Med Clin (Barc) 2010, 135:397-401.
  • [5]Ozawa M, Tamura K, Okano Y, Matsushita K, Ikeya Y, et al.: Blood pressure variability as well as blood pressure level is important for left ventricular hypertrophy and brachial-ankle pulse wave velocity in hypertensives. Clin Exp Hypertens 2009, 31:669-679.
  • [6]Schirmer H, Lunde P, Rasmussen K: Prevalence of left ventricular hypertrophy in a general population; The Tromso Study. Eur Heart J 1999, 20:429-438.
  • [7]Castro MG, Rodriguez-Pascual F, Magan-Marchal N, Reguero JR, Alonso-Montes C, et al.: Screening of the endothelin1 gene (EDN1) in a cohort of patients with essential left ventricular hypertrophy. Ann Hum Genet 2007, 71:601-610.
  • [8]Bella JN, Goring HH: Genetic epidemiology of left ventricular hypertrophy. Am J Cardiovasc Dis 2012, 2:267-278.
  • [9]Arnett DK: Genetic contributions to left ventricular hypertrophy. Curr Hypertens Rep 2000, 2:50-55.
  • [10]Hogan BL: Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 1996, 10:1580-1594.
  • [11]Chang SF, Chang TK, Peng HH, Yeh YT, Lee DY, et al.: BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21 CIP1 and p27 KIP1 regulation. Mol Endocrinol 2009, 23:1827-1838.
  • [12]Wang Y, Hou X, Li Y: Association between transforming growth factor beta1 polymorphisms and atrial fibrillation in essential hypertensive subjects. J Biomed Sci 2010, 17:23. BioMed Central Full Text
  • [13]Xu HY, Hou XW, Wang LF, Wang NF, Xu J: Association between transforming growth factor beta1 polymorphisms and left ventricle hypertrophy in essential hypertensive subjects. Mol Cell Biochem 2010, 335:13-17.
  • [14]Zhang Y, Liu J, Tian XY, Wong WT, Chen Y, et al.: Inhibition of bone morphogenic protein 4 restores endothelial function in db/db diabetic mice. Arterioscler Thromb Vasc Biol 2014, 34:152-159.
  • [15]Wong WT, Tian XY, Chen Y, Leung FP, Liu L, et al.: Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension. Circ Res 2010, 107:984-991.
  • [16]Hosseinkhani M, Hosseinkhani H, Khademhosseini A, Bolland F, Kobayashi H, et al.: Bone morphogenetic protein-4 enhances cardiomyocyte differentiation of cynomolgus monkey ESCs in knockout serum replacement medium. Stem Cells 2007, 25:571-580.
  • [17]Pachori AS, Custer L, Hansen D, Clapp S, Kemppa E, et al.: Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol 2010, 48:1255-1265.
  • [18]Wu X, Sagave J, Rutkovskiy A, Haugen F, Baysa A, et al.: Expression of bone morphogenetic protein 4 and its receptors in the remodeling heart. Life Sci 2014, 97:145-154.
  • [19]Sun B, Huo R, Sheng Y, Li Y, Xie X, et al.: Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension 2013, 61:352-360.
  • [20]Lin JY, Chen YJ, Huang YL, Tang GP, Zhang L, et al.: Association of bone morphogenetic protein 4 gene polymorphisms with nonsyndromic cleft lip with or without cleft palate in Chinese children. DNA Cell Biol 2008, 27:601-605.
  • [21]Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, et al.: RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 2009, 104:1041-1048.
  • [22]Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, et al.: Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J Biol Chem 2003, 278:31128-31135.
  • [23]Valera ET, Brassesco MS, Scrideli CA, de Castro Barros MV, Santos AC, et al.: Are patients with encephalocraniocutaneous lipomatosis at increased risk of developing low-grade gliomas? Childs Nerv Syst 2012, 28:19-22.
  • [24]Xian S, Jilu L, Zhennan T, Yang Z, Yang H, et al.: BMP-4 genetic variants and protein expression are associated with platinum-based chemotherapy response and prognosis in NSCLC. Biomed Res Int 2014, 2014:801640.
  • [25]Stahls PF 3rd, Lightell DJ Jr, Moss SC, Goldman CK, Woods TC: Elevated serum bone morphogenetic protein 4 in patients with chronic kidney disease and coronary artery disease. J Cardiovasc Transl Res 2013, 6:232-238.
  • [26]Hou X, Hu Z, Huang X, Chen Y, He X, et al.: Serum osteopontin, but not OPN gene polymorphism, is associated with LVH in essential hypertensive patients. J Mol Med (Berl) 2014, 92:487-495.
  • [27]Su FF, Shi MQ, Guo WG, Liu XT, Wang HT, et al.: High-mobility group box 1 induces calcineurin-mediated cell hypertrophy in neonatal rat ventricular myocytes. Mediators Inflamm 2012, 2012:805149.
  • [28]Miriyala S, Gongora Nieto MC, Mingone C, Smith D, Dikalov S, et al.: Bone morphogenic protein-4 induces hypertension in mice: role of noggin, vascular NADPH oxidases, and impaired vasorelaxation. Circulation 2006, 113:2818-2825.
  • [29]Sainger R, Grau JB, Branchetti E, Poggio P, Seefried WF, et al.: Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. J Cell Physiol 2012, 227:2595-2604.
  • [30]Hu CW, Li Q, Zhang Y, Li YH, Jiang HC, et al. Bone morphogenetic protein-4 induces upregulation of Cav3.1 Ca channels in HL-1 atrial myocytes. Pflugers Arch. 2014;
  • [31]Ramesh Babu L, Wilson SG, Dick IM, Islam FM, Devine A, et al.: Bone mass effects of a BMP4 gene polymorphism in postmenopausal women. Bone 2005, 36:555-561.
  • [32]Capasso M, Ayala F, Russo R, Avvisati RA, Asci R, et al.: A predicted functional single-nucleotide polymorphism of bone morphogenetic protein-4 gene affects mRNA expression and shows a significant association with cutaneous melanoma in Southern Italian population. J Cancer Res Clin Oncol 2009, 135:1799-1807.
  • [33]Goracy I, Safranow K, Dawid G, Skonieczna-Zydecka K, Kaczmarczyk M, et al.: Common genetic variants of the BMP4, BMPR1A, BMPR1B, and ACVR1 genes, left ventricular mass, and other parameters of the heart in newborns. Genet Test Mol Biomarkers 2012, 16:1309-1316.
  • [34]Li X, Zhu H, Li P, Xin Q, Liu J, et al.: Serum cystatin C concentration as an independent marker for hypertensive left ventricular hypertrophy. J Geriatr Cardiol 2013, 10:286-290.
  • [35]Watanabe S, Okura T, Liu J, Miyoshi K, Fukuoka T, et al.: Serum cystatin C level is a marker of end-organ damage in patients with essential hypertension. Hypertens Res 2003, 26:895-899.
  • [36]Agrinier N, Thilly N, Boivin JM, Dousset B, Alla F, et al.: Prognostic value of serum PIIINP, MMP1 and TIMP1 levels in hypertensive patients: a community-based prospective cohort study. Fundam Clin Pharmacol 2013, 27:572-580.
  • [37]Shi B, Ni Z, Cai H, Zhang M, Mou S, et al.: High-sensitivity C-reactive protein: an independent risk factor for left ventricular hypertrophy in patients with lupus nephritis. J Biomed Biotechnol 2010, 2010:373426.
  • [38]Monfared A, Salari A, Kazemnezhad E, Lebadi M, Khosravi M, et al.: Association of left ventricular hypertrophy with high-sensitive C-reactive protein in hemodialysis patients. Int Urol Nephrol 2013, 45:1679-1686.
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