J Mol Med (2014) 92:487–495 DOI 10.1007/s00109-013-1099-9
ORIGINAL ARTICLE
Serum osteopontin, but not OPN gene polymorphism, is associated with LVH in essential hypertensive patients Xuwei Hou & Zhaohui Hu & Xiaohua Huang & Yan Chen & Xiuying He & Haiying Xu & Ningfu Wang
Received: 7 July 2013 / Revised: 24 September 2013 / Accepted: 31 October 2013 / Published online: 27 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract This study aims to investigate the role of osteopontin (OPN) genetic polymorphisms in the occurrence of left ventricular hypertrophy (LVH) in Chinese patients with essential hypertension (EH). A total of 1,092 patients diagnosed with EH were recruited. Three single nucleotide polymorphisms (SNP) on the promoter region of the OPN gene, including −66T/G, −156G/GG, and −443C/T were genotyped. The serum thrombin-cleaved OPN levels were studied. Patients were divided into LVH+ (n =443) and the LVH− (n =649) groups. We found that none of the studied SNPs in the OPN gene was associated with the risk and severity of LVH. The SNPs in the OPN gene did not correlate with the serum OPN levels. However, the serum thrombin-cleaved OPN levels were found to be an independent risk factor for LVH in the EH patients. Multivariate logistic regression analysis showed that serum thrombin-cleaved OPN levels were independently associated with the development of LVH (adjusted OR=
2.47, 95 % CI 1.56–4.01, adjusted P 49.2 g/2.7 m for men and >46.7 g/2.7 m for women [10]. The two investigators who were blind to the study design performed the measurements of LV wall thickness independently for all enrolled subjects. The intra-observer correlation coefficiency of two interviewers was 0.871 (P 0.05)
a
ng/ml
60
30
0
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
b
ng/ml
200
100
0
c LVMI(g/m2)l
60
30
0
compared to the LVH− group, but did not reach significant difference. The duration to diagnosis of EH and therapy duration were similar between LVH+ and LVH− groups. Smoking occurred more frequently among the LVH+ patients than the LVH− patients. No significant difference was noted between the LVH+ and LVH− groups in the antihypertensive medication. The mean LVMI was 51.3±3.8 g/m2 in the LVH+ group
Table 3 The thrombin-cleaved OPN levels in individuals with or without angiotensin II blockade
With angiotensin II blockade Without angiotensin II blockade P value
LVH+
LVH−
148.4±27.9 158±21.5 0.055
97±28.4 104±20.9 0.058
whereas the mean LVMI was 43.3±4.1 g/m2 in the LVH− group (P 0.05). No significant difference was observed in the genotype and allele frequencies of the 443C>T, −156/ G>GG and −66T>G polymorphisms between the LVH+ and LVH− subgroups (all P >0.05). We then performed the multivariate logistic regression analysis to determine if the OPN genetic polymorphisms were associated with the risk to develop LVH after adjustment of confounding risk factors, such as age, sex, smoking status, BMI, TG, TC, HDL-C, LDL-C, HBP, and DBP levels. Multivariate logistic regression analysis did not reveal any significant association between those polymorphisms and the incidence of LVH.
492
Fig. 2 The ROC curve (solid line) to determine LVH using the serum thrombin-cleaved OPN. At a cutoff value of 176.8 ng/ml, the area under curve (AUC) for thrombin-cleaved OPN was 0.980 (95 % CI 0.945– 0.993, P =0.018, with specificity of 82.3 % and sensitivity of 87.7 %). Previous studies suggest that hs-CRP is also a predictor for LVH; however, our study did not support this notion (dashed line). The AUG of hsCRP was 0.791 (95 % CI 0.628-0.925, P =0.068)
The association between full-length OPN and thrombincleaved OPN levels and LVMI were compared according to the OPN genotypes. We did not find statistically significant differences in the OPN and LVMI levels in association with different OPN genotype carriers (Fig. 1a–c). We next investigated serum full-length OPN and thrombincleaved OPN levels based on the presence or absence of LVH. The mean serum full-length OPN levels were similar between the LVH+ and LVH− groups (45.7±16.5 vs. 44.7±17.5 ng/ ml, P =0.453). However, the mean serum OPN levels were significantly higher in the LVH+ group (154.1±33.6 ng/ml) than in the LVH− group (102.1±26.7 ng/ml, P T was associated with increased intima-media thickness in
stroke patients [35]. However, in this study, we did not find positive correlation between OPN and the risk and severity of LVH in EH patients. Three studied OPN loci were not associated with the mean serum OPN levels. Similar results were also observed in Chinese patients with Behçet's disease. The serum OPN level was associated with clinical severity of the disease; however, the prevalence of OPN gene polymorphisms did not correlate with the incidence and severity of the disease [36]. In patients with rheumatoid arthritis (RA), OPN gene expression was significantly increased in synovial fluid mononuclear cells and peripheral blood mononuclear cells compared to controls. In this study, the prevalence of OPN genotype and allele frequencies at the selected positions did not significantly differ between the RA patients and the control group (P >0.05) [37]. We did not investigate whether the OPN gene polymorphism may change the expression of myocardial OPN in EH patients, as cardiac biopsy samples were not available due to the ethnic reason. Recent studies reported that −66 polymorphism modifies the binding affinity for the SP1/SP3 transcription factors in
494
cultured HeLa cells, the −156 polymorphism is located in a yet uncharacterized RUNX2 binding site, and the −443 polymorphism may bind to an unknown factor [38]. In patients with knee osteoarthritis, the polymorphisms of −443C/T and −66T/ G significantly affected the thrombin-cleaved OPN levels from the synovial fluid of patients. Subjects with −443TT and −66GG genotypes had lower thrombin-cleaved OPN levels in synovial fluid [24]. In this study, we did not observe significant correlation between the OPN levels and any studied SNPs. The discrepancy may be due to the different cell types studied, or to different pathological conditions among the enrolled cohorts. Thus, more detailed research is entailed to elucidate the association between the OPN polymorphisms and the expression level of the OPN protein. In this study, we detected full-length and thrombincleaved OPN levels in serum using the ELISA method, which has been well documented [23, 24]. Previous studies suggest that OPN contains both the thrombin cleavage sites and the matrix metalloproteinase (MMP) cleavage sites [39–41]. The thrombin-cleaved OPN and the “matrix MMPactivated” OPN forms have different integrin binding domains. The recruitment functions of OPN for inflammatory cells may be mediated through its adhesive domains interacting with several integrin heterodimers [42]. The thrombin-cleaved fragment has an additional cell interacting domain (SVVYGLR) compared with the MMP-cleaved fragment. Based on the multi-domain structure of the OPN and the existence of active OPN cleavage products, the forms of OPN, the thrombin, and MMPs serum levels should be analyzed. In our study, the thrombin-cleaved OPN was shown to dramatically affect the cardiomyocyte surface size and the expression level of ANP. However, a broader unbiased investigation with serum proteomic analysis is currently absent. This is a major limitation of this study. To investigate the direct effect of thrombin-cleaved OPN on cardiomyocyte hypertrophy in vitro, we studied cardiomyocyte from neonatal rats and treated cells with different levels of thrombin-cleaved OPN. We found that the in vitro thrombin-cleaved OPN treatment increased the protein expression levels, surface size, and the ANP protein expression levels in a dose-dependent manner, which were consistent with our clinical observations in this study. In conclusion, we reported OPN as a new serum marker to predict the development of LVH in EH patients. The OPN gene polymorphisms were not associated with the development of LVH. However, a larger-scale validation study is warranted. Acknowledgments This study was supported by the grant of “Qianjiang Rencai project” from Zhejiang province (2010 D). Conflict of interest The authors declare no conflict of interests related to this study.
J Mol Med (2014) 92:487–495
References 1. Zhan S, Liu M, Yao W, Hu Y, Li L, Zhu G, Sun N, Dai L (2002) Prevalence and relevant factors on echocardiographic left ventricular hypertrophy among community-based hypertensive patients in Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi 23(3):182–185 2. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano FQ, Giannattasio C, Grassi G, Sega R (2008) Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population. J Hypertens 26(8):1602–1611 3. Petrovic D, Stojimirovic B (2008) Left ventricular hypertrophy in patients treated with regular hemodialyses. Med Pregl 61(7–8):369– 374 4. Kaplinsky E (1994) Significance of left ventricular hypertrophy in cardiovascular morbidity and mortality. Cardiovasc Drugs Ther 8(Suppl 3):549–556 5. Tovillas-Moran FJ, Vilaplana-Cosculluela M, Zabaleta-del-Olmo E, Dalfo-Baque A, Galceran JM, Coca A (2010) Cardiovascular morbidity and mortality and electrocardiographic criteria of left ventricular hypertrophy in hypertensive patients treated in primary care. Med Clin (Barc) 135(9):397–401 6. Ozawa M, Tamura K, Okano Y, Matsushita K, Ikeya Y, Masuda S, Wakui H, Dejima T, Shigenaga A, Azuma K et al (2009) 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 31(8):669–679 7. Schirmer H, Lunde P, Rasmussen K (1999) Prevalence of left ventricular hypertrophy in a general population: the Tromso Study. Eur Heart J 20(6):429–438 8. Bella JN, Goring HH (2012) Genetic epidemiology of left ventricular hypertrophy. Am J Cardiovasc Dis 2(4):267–278 9. Arnett DK (2000) Genetic contributions to left ventricular hypertrophy. Curr Hypertens Rep 2(1):50–55 10. Xu HY, Hou XW, Wang LF, Wang NF, Xu J (2010) Association between transforming growth factor beta1 polymorphisms and left ventricle hypertrophy in essential hypertensive subjects. Mol Cell Biochem 335(1–2):13–17 11. Kurbanova D, Eliseyeva M (2010) Genetic background of left ventricular hypertrophy in Uzbek hypertensive men. Turk Kardiyol Dern Ars 38(7):466–472 12. El-Shehaby AM, El-Khatib MM, Marzouk S, Battah AA (2012) Relationship of BsmI polymorphism of vitamin D receptor gene with left ventricular hypertrophy and atherosclerosis in hemodialysis patients. Scand J Clin Lab Invest 73(1):75−81 13. Kaufman BD, Desai M, Reddy S, Osorio JC, Chen JM, Mosca RS, Ferrante AW, Mital S (2008) Genomic profiling of left and right ventricular hypertrophy in congenital heart disease. J Card Fail 14(9):760–767 14. Giachelli CM, Steitz S (2000) Osteopontin: a versatile regulator of inflammation and biomineralization. Matrix Biol 19(7):615–622 15. Wolak T, Kim H, Ren Y, Kim J, Vaziri ND, Nicholas SB (2009) Osteopontin modulates angiotensin II-induced inflammation, oxidative stress, and fibrosis of the kidney. Kidney Int 76(1):32–43 16. Dahiya S, Givvimani S, Bhatnagar S, Qipshidze N, Tyagi SC, Kumar A (2011) Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy. J Immunol 187(5):2723–2731 17. Rosenberg M, Meyer FJ, Gruenig E, Lutz M, Lossnitzer D, Wipplinger R, Katus HA, Frey N (2012) Osteopontin predicts adverse right ventricular remodelling and dysfunction in pulmonary hypertension. Eur J Clin Investig 42(9):933–942 18. Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA (1997) Myocardial osteopontin expression
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495 31. Francia P, Balla C, Ricotta A, Uccellini A, Frattari A, Modestino A, Borro M, Simmaco M, Salvati A, De Biase L et al (2011) Plasma osteopontin reveals left ventricular reverse remodelling following cardiac resynchronization therapy in heart failure. Int J Cardiol 153(3):306–310 32. Schipper ME, Scheenstra MR, van Kuik J, van Wichen DF, van der Weide P, Dullens HF, Lahpor J, de Jonge N, De Weger RA (2011) Osteopontin: a potential biomarker for heart failure and reverse remodeling after left ventricular assist device support. J Heart Lung Transplant 30(7):805–810 33. Nakayama H, Nagai H, Matsumoto K, Oguro R, Sugimoto K, Kamide K, Ohishi M, Katsuya T, Okamoto H, Maeda M et al (2011) Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population. Hypertens Res 34(10):1141–1146 34. de las Fuentes L, Gu CC, Mathews SJ, Reagan JL, Ruthmann NP, Waggoner AD, Lai CF, Towler DA, Davila-Roman VG (2008) Osteopontin promoter polymorphism is associated with increased carotid intima-media thickness. J Am Soc Echocardiogr 21(8):954–960 35. Brenner D, Labreuche J, Touboul PJ, Schmidt-Petersen K, Poirier O, Perret C, Schonfelder J, Combadiere C, Lathrop M, Cambien F et al (2006) Cytokine polymorphisms associated with carotid intimamedia thickness in stroke patients. Stroke 37(7):1691–1696 36. Chu M, Yang P, Hou S, Li F, Chen Y, Kijlstra A (2011) Behcet's disease exhibits an increased osteopontin serum level in active stage but no association with osteopontin and its receptor gene polymorphisms. Hum Immunol 72(6):525–529 37. Xu G, Sun W, He D, Wang L, Zheng W, Nie H, Ni L, Zhang D, Li N, Zhang J (2005) Overexpression of osteopontin in rheumatoid synovial mononuclear cells is associated with joint inflammation, not with genetic polymorphism. J Rheumatol 32(3):410–416 38. Chiu YW, Tu HF, Wang IK, Wu CH, Chang KW, Liu TY, Kao SY (2010) The implication of osteopontin (OPN) expression and genetic polymorphisms of OPN promoter in oral carcinogenesis. Oral Oncol 46(4):302–306 39. Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Schneider H, Higashiyama S, Saitoh Y, Yamakido M, Taooka Y, Sheppard D (1999) The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. J Biol Chem 274(51):36328–36334 40. Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L (2001) Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem 276(30):28261–28267 41. Hou P, Troen T, Ovejero MC, Kirkegaard T, Andersen TL, Byrjalsen I, Ferreras M, Sato T, Shapiro SD, Foged NT et al (2004) Matrix metalloproteinase-12 (MMP-12) in osteoclasts: new lesson on the involvement of MMPs in bone resorption. Bone 34(1):37–47 42. Scatena M, Liaw L, Giachelli CM (2007) Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 27(11):2302–2309
ORIGINAL ARTICLE
Serum osteopontin, but not OPN gene polymorphism, is associated with LVH in essential hypertensive patients Xuwei Hou & Zhaohui Hu & Xiaohua Huang & Yan Chen & Xiuying He & Haiying Xu & Ningfu Wang
Received: 7 July 2013 / Revised: 24 September 2013 / Accepted: 31 October 2013 / Published online: 27 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract This study aims to investigate the role of osteopontin (OPN) genetic polymorphisms in the occurrence of left ventricular hypertrophy (LVH) in Chinese patients with essential hypertension (EH). A total of 1,092 patients diagnosed with EH were recruited. Three single nucleotide polymorphisms (SNP) on the promoter region of the OPN gene, including −66T/G, −156G/GG, and −443C/T were genotyped. The serum thrombin-cleaved OPN levels were studied. Patients were divided into LVH+ (n =443) and the LVH− (n =649) groups. We found that none of the studied SNPs in the OPN gene was associated with the risk and severity of LVH. The SNPs in the OPN gene did not correlate with the serum OPN levels. However, the serum thrombin-cleaved OPN levels were found to be an independent risk factor for LVH in the EH patients. Multivariate logistic regression analysis showed that serum thrombin-cleaved OPN levels were independently associated with the development of LVH (adjusted OR=
2.47, 95 % CI 1.56–4.01, adjusted P 49.2 g/2.7 m for men and >46.7 g/2.7 m for women [10]. The two investigators who were blind to the study design performed the measurements of LV wall thickness independently for all enrolled subjects. The intra-observer correlation coefficiency of two interviewers was 0.871 (P 0.05)
a
ng/ml
60
30
0
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
CC
CT TT 443C>T
GG GGG GGGG -156G>GG
TT
TG GG -66T>G
b
ng/ml
200
100
0
c LVMI(g/m2)l
60
30
0
compared to the LVH− group, but did not reach significant difference. The duration to diagnosis of EH and therapy duration were similar between LVH+ and LVH− groups. Smoking occurred more frequently among the LVH+ patients than the LVH− patients. No significant difference was noted between the LVH+ and LVH− groups in the antihypertensive medication. The mean LVMI was 51.3±3.8 g/m2 in the LVH+ group
Table 3 The thrombin-cleaved OPN levels in individuals with or without angiotensin II blockade
With angiotensin II blockade Without angiotensin II blockade P value
LVH+
LVH−
148.4±27.9 158±21.5 0.055
97±28.4 104±20.9 0.058
whereas the mean LVMI was 43.3±4.1 g/m2 in the LVH− group (P 0.05). No significant difference was observed in the genotype and allele frequencies of the 443C>T, −156/ G>GG and −66T>G polymorphisms between the LVH+ and LVH− subgroups (all P >0.05). We then performed the multivariate logistic regression analysis to determine if the OPN genetic polymorphisms were associated with the risk to develop LVH after adjustment of confounding risk factors, such as age, sex, smoking status, BMI, TG, TC, HDL-C, LDL-C, HBP, and DBP levels. Multivariate logistic regression analysis did not reveal any significant association between those polymorphisms and the incidence of LVH.
492
Fig. 2 The ROC curve (solid line) to determine LVH using the serum thrombin-cleaved OPN. At a cutoff value of 176.8 ng/ml, the area under curve (AUC) for thrombin-cleaved OPN was 0.980 (95 % CI 0.945– 0.993, P =0.018, with specificity of 82.3 % and sensitivity of 87.7 %). Previous studies suggest that hs-CRP is also a predictor for LVH; however, our study did not support this notion (dashed line). The AUG of hsCRP was 0.791 (95 % CI 0.628-0.925, P =0.068)
The association between full-length OPN and thrombincleaved OPN levels and LVMI were compared according to the OPN genotypes. We did not find statistically significant differences in the OPN and LVMI levels in association with different OPN genotype carriers (Fig. 1a–c). We next investigated serum full-length OPN and thrombincleaved OPN levels based on the presence or absence of LVH. The mean serum full-length OPN levels were similar between the LVH+ and LVH− groups (45.7±16.5 vs. 44.7±17.5 ng/ ml, P =0.453). However, the mean serum OPN levels were significantly higher in the LVH+ group (154.1±33.6 ng/ml) than in the LVH− group (102.1±26.7 ng/ml, P T was associated with increased intima-media thickness in
stroke patients [35]. However, in this study, we did not find positive correlation between OPN and the risk and severity of LVH in EH patients. Three studied OPN loci were not associated with the mean serum OPN levels. Similar results were also observed in Chinese patients with Behçet's disease. The serum OPN level was associated with clinical severity of the disease; however, the prevalence of OPN gene polymorphisms did not correlate with the incidence and severity of the disease [36]. In patients with rheumatoid arthritis (RA), OPN gene expression was significantly increased in synovial fluid mononuclear cells and peripheral blood mononuclear cells compared to controls. In this study, the prevalence of OPN genotype and allele frequencies at the selected positions did not significantly differ between the RA patients and the control group (P >0.05) [37]. We did not investigate whether the OPN gene polymorphism may change the expression of myocardial OPN in EH patients, as cardiac biopsy samples were not available due to the ethnic reason. Recent studies reported that −66 polymorphism modifies the binding affinity for the SP1/SP3 transcription factors in
494
cultured HeLa cells, the −156 polymorphism is located in a yet uncharacterized RUNX2 binding site, and the −443 polymorphism may bind to an unknown factor [38]. In patients with knee osteoarthritis, the polymorphisms of −443C/T and −66T/ G significantly affected the thrombin-cleaved OPN levels from the synovial fluid of patients. Subjects with −443TT and −66GG genotypes had lower thrombin-cleaved OPN levels in synovial fluid [24]. In this study, we did not observe significant correlation between the OPN levels and any studied SNPs. The discrepancy may be due to the different cell types studied, or to different pathological conditions among the enrolled cohorts. Thus, more detailed research is entailed to elucidate the association between the OPN polymorphisms and the expression level of the OPN protein. In this study, we detected full-length and thrombincleaved OPN levels in serum using the ELISA method, which has been well documented [23, 24]. Previous studies suggest that OPN contains both the thrombin cleavage sites and the matrix metalloproteinase (MMP) cleavage sites [39–41]. The thrombin-cleaved OPN and the “matrix MMPactivated” OPN forms have different integrin binding domains. The recruitment functions of OPN for inflammatory cells may be mediated through its adhesive domains interacting with several integrin heterodimers [42]. The thrombin-cleaved fragment has an additional cell interacting domain (SVVYGLR) compared with the MMP-cleaved fragment. Based on the multi-domain structure of the OPN and the existence of active OPN cleavage products, the forms of OPN, the thrombin, and MMPs serum levels should be analyzed. In our study, the thrombin-cleaved OPN was shown to dramatically affect the cardiomyocyte surface size and the expression level of ANP. However, a broader unbiased investigation with serum proteomic analysis is currently absent. This is a major limitation of this study. To investigate the direct effect of thrombin-cleaved OPN on cardiomyocyte hypertrophy in vitro, we studied cardiomyocyte from neonatal rats and treated cells with different levels of thrombin-cleaved OPN. We found that the in vitro thrombin-cleaved OPN treatment increased the protein expression levels, surface size, and the ANP protein expression levels in a dose-dependent manner, which were consistent with our clinical observations in this study. In conclusion, we reported OPN as a new serum marker to predict the development of LVH in EH patients. The OPN gene polymorphisms were not associated with the development of LVH. However, a larger-scale validation study is warranted. Acknowledgments This study was supported by the grant of “Qianjiang Rencai project” from Zhejiang province (2010 D). Conflict of interest The authors declare no conflict of interests related to this study.
J Mol Med (2014) 92:487–495
References 1. Zhan S, Liu M, Yao W, Hu Y, Li L, Zhu G, Sun N, Dai L (2002) Prevalence and relevant factors on echocardiographic left ventricular hypertrophy among community-based hypertensive patients in Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi 23(3):182–185 2. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano FQ, Giannattasio C, Grassi G, Sega R (2008) Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population. J Hypertens 26(8):1602–1611 3. Petrovic D, Stojimirovic B (2008) Left ventricular hypertrophy in patients treated with regular hemodialyses. Med Pregl 61(7–8):369– 374 4. Kaplinsky E (1994) Significance of left ventricular hypertrophy in cardiovascular morbidity and mortality. Cardiovasc Drugs Ther 8(Suppl 3):549–556 5. Tovillas-Moran FJ, Vilaplana-Cosculluela M, Zabaleta-del-Olmo E, Dalfo-Baque A, Galceran JM, Coca A (2010) Cardiovascular morbidity and mortality and electrocardiographic criteria of left ventricular hypertrophy in hypertensive patients treated in primary care. Med Clin (Barc) 135(9):397–401 6. Ozawa M, Tamura K, Okano Y, Matsushita K, Ikeya Y, Masuda S, Wakui H, Dejima T, Shigenaga A, Azuma K et al (2009) 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 31(8):669–679 7. Schirmer H, Lunde P, Rasmussen K (1999) Prevalence of left ventricular hypertrophy in a general population: the Tromso Study. Eur Heart J 20(6):429–438 8. Bella JN, Goring HH (2012) Genetic epidemiology of left ventricular hypertrophy. Am J Cardiovasc Dis 2(4):267–278 9. Arnett DK (2000) Genetic contributions to left ventricular hypertrophy. Curr Hypertens Rep 2(1):50–55 10. Xu HY, Hou XW, Wang LF, Wang NF, Xu J (2010) Association between transforming growth factor beta1 polymorphisms and left ventricle hypertrophy in essential hypertensive subjects. Mol Cell Biochem 335(1–2):13–17 11. Kurbanova D, Eliseyeva M (2010) Genetic background of left ventricular hypertrophy in Uzbek hypertensive men. Turk Kardiyol Dern Ars 38(7):466–472 12. El-Shehaby AM, El-Khatib MM, Marzouk S, Battah AA (2012) Relationship of BsmI polymorphism of vitamin D receptor gene with left ventricular hypertrophy and atherosclerosis in hemodialysis patients. Scand J Clin Lab Invest 73(1):75−81 13. Kaufman BD, Desai M, Reddy S, Osorio JC, Chen JM, Mosca RS, Ferrante AW, Mital S (2008) Genomic profiling of left and right ventricular hypertrophy in congenital heart disease. J Card Fail 14(9):760–767 14. Giachelli CM, Steitz S (2000) Osteopontin: a versatile regulator of inflammation and biomineralization. Matrix Biol 19(7):615–622 15. Wolak T, Kim H, Ren Y, Kim J, Vaziri ND, Nicholas SB (2009) Osteopontin modulates angiotensin II-induced inflammation, oxidative stress, and fibrosis of the kidney. Kidney Int 76(1):32–43 16. Dahiya S, Givvimani S, Bhatnagar S, Qipshidze N, Tyagi SC, Kumar A (2011) Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy. J Immunol 187(5):2723–2731 17. Rosenberg M, Meyer FJ, Gruenig E, Lutz M, Lossnitzer D, Wipplinger R, Katus HA, Frey N (2012) Osteopontin predicts adverse right ventricular remodelling and dysfunction in pulmonary hypertension. Eur J Clin Investig 42(9):933–942 18. Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA (1997) Myocardial osteopontin expression
J Mol Med (2014) 92:487–495
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