CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 05 2020
29 05 2020
Historique:
received:
18
09
2019
accepted:
03
05
2020
entrez:
31
5
2020
pubmed:
31
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4-6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis.
Identifiants
pubmed: 32472014
doi: 10.1038/s41598-020-65601-0
pii: 10.1038/s41598-020-65601-0
pmc: PMC7260244
doi:
Substances chimiques
Steroids
0
Steroid 17-alpha-Hydroxylase
EC 1.14.14.19
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8792Références
Mozaffarian, D. et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 133, e38–360 (2016).
pubmed: 26673558
Erdmann, J., Kessler, T., Munoz Venegas, L. & Schunkert, H. A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res 114, 1241–1257 (2018).
pubmed: 29617720
IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet 7, e1002260 (2011).
Hotta, K. et al. Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women. J Hum Genet 57, 46–51 (2012).
pubmed: 22071413
doi: 10.1038/jhg.2011.127
Pang, S. Y. et al. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81, 866–74 (1988).
pubmed: 3259306
Marsh, C. A. & Auchus, R. J. Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Fertil Steril 101, 317–22 (2014).
Costa-Santos, M., Kater, C. E. & Auchus, R. J., Brazilian Congenital Adrenal Hyperplasia Multicenter Study, G. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab 89, 49–60 (2004).
pubmed: 14715827
doi: 10.1210/jc.2003-031021
Krone, N. & Arlt, W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23, 181–92 (2009).
pubmed: 19500762
doi: 10.1016/j.beem.2008.10.014
Miller, W. L. Mechanisms In Endocrinology: Rare defects in adrenal steroidogenesis. Eur J Endocrinol 179, R125–R141 (2018).
pubmed: 29880708
doi: 10.1530/EJE-18-0279
Nakajin, S., Hall, P. F. & Onoda, M. Testicular microsomal cytochrome P-450 for C21 steroid side chain cleavage. Spectral and binding studies. J Biol Chem 256, 6134–9 (1981).
pubmed: 7240194
Nakajin, S., Shively, J. E., Yuan, P. M. & Hall, P. F. Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17 alpha-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry 20, 4037–42 (1981).
pubmed: 6793062
doi: 10.1021/bi00517a014
Bairey Merz, C. N. et al. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol 41, 413–9 (2003).
pubmed: 12575968
doi: 10.1016/S0735-1097(02)02763-8
Nasri, H., Mayel, Y., Sheikhvatan, M. & Forood, A. Premature menopause and severity of coronary artery disease. J Res Med Sci 16, 1026–31 (2011).
pubmed: 22279478
pmcid: 3263079
Parker, W. H. et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol 113, 1027–37 (2009).
pubmed: 19384117
pmcid: 3791619
doi: 10.1097/AOG.0b013e3181a11c64
Rivera, C. M. et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 16, 15–23 (2009).
pubmed: 19034050
pmcid: 2755630
doi: 10.1097/gme.0b013e31818888f7
Sudhir, K. & Komesaroff, P. A. Clinical review 110: Cardiovascular actions of estrogens in men. J Clin Endocrinol Metab 84, 3411–5 (1999).
pubmed: 10522972
doi: 10.1210/jcem.84.10.5954
Klaiber, E. L. et al. Serum estrogen levels in men with acute myocardial infarction. Am J Med 73, 872–81 (1982).
pubmed: 7148879
doi: 10.1016/0002-9343(82)90779-3
Laughlin, G. A., Barrett-Connor, E. & Bergstrom, J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 93, 68–75 (2008).
pubmed: 17911176
doi: 10.1210/jc.2007-1792
Shores, M. M., Matsumoto, A. M., Sloan, K. L. & Kivlahan, D. R. Low serum testosterone and mortality in male veterans. Arch Intern Med 166, 1660–5 (2006).
pubmed: 16908801
doi: 10.1001/archinte.166.15.1660
Wilhelmson, A. S. et al. Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells-Brief Report. Arterioscler Thromb Vasc Biol 38, 1519–1527 (2018).
pubmed: 29853568
pmcid: 6039408
doi: 10.1161/ATVBAHA.118.311252
Aherrahrou, Z. et al. An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H/He mice. J Biol Chem 283, 7608–15 (2008).
pubmed: 18201967
doi: 10.1074/jbc.M708290200
Kessler, T. et al. ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1. Circulation 131, 1191–201 (2015).
pubmed: 25712208
doi: 10.1161/CIRCULATIONAHA.114.014072
Sowa, A. K. et al. Functional interaction of osteogenic transcription factors Runx2 and Vdr in transcriptional regulation of Opn during soft tissue calcification. Am J Pathol 183, 60–8 (2013).
pubmed: 23644099
doi: 10.1016/j.ajpath.2013.03.007
Segura-Puimedon, M. et al. Proatherosclerotic Effect of the alpha1-Subunit of Soluble Guanylyl Cyclase by Promoting Smooth Muscle Phenotypic Switching. Am J Pathol 186, 2220–2231 (2016).
pubmed: 27315776
doi: 10.1016/j.ajpath.2016.04.010
Pellegrino, R. M., Di Veroli, A., Valeri, A., Goracci, L. & Cruciani, G. LC/MS lipid profiling from human serum: a new method for global lipid extraction. Anal Bioanal Chem 406, 7937–48 (2014).
pubmed: 25381612
doi: 10.1007/s00216-014-8255-0
Narvaez-Rivas, M. & Zhang, Q. Comprehensive untargeted lipidomic analysis using core-shell C30 particle column and high field orbitrap mass spectrometer. J Chromatogr A 1440, 123–134 (2016).
pubmed: 26928874
pmcid: 4792668
doi: 10.1016/j.chroma.2016.02.054
Karsai, G. et al. DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans. J Clin Invest (2019).
Kulle, A. E., Riepe, F. G., Melchior, D., Hiort, O. & Holterhus, P. M. A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone, and dihydrotestosterone in pediatric blood samples: age- and sex-specific reference data. J Clin Endocrinol Metab 95, 2399–409 (2010).
pubmed: 20200336
doi: 10.1210/jc.2009-1670
Kulle, A. E., Welzel, M., Holterhus, P. M. & Riepe, F. G. Implementation of a liquid chromatography tandem mass spectrometry assay for eight adrenal C-21 steroids and pediatric reference data. Horm Res Paediatr 79, 22–31 (2013).
pubmed: 23328487
doi: 10.1159/000346406
Auchus, R. J. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol 165, 71–78 (2017).
pubmed: 26862015
doi: 10.1016/j.jsbmb.2016.02.002
Gamazon, E. R. et al. Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat Genet 50, 956–967 (2018).
pubmed: 29955180
pmcid: 6248311
doi: 10.1038/s41588-018-0154-4
Dai, C. F. et al. The relationship between the polymorphisms of the CYP17A1 gene and hypertension: A meta-analysis. J Renin Angiotensin Aldosterone Syst 16, 1314–20 (2015).
pubmed: 25990650
doi: 10.1177/1470320315585683
Diver, L. A. et al. Common Polymorphisms at the CYP17A1 Locus Associate With Steroid Phenotype: Support for Blood Pressure Genome-Wide Association Study Signals at This Locus. Hypertension 67, 724–732 (2016).
pubmed: 26902494
pmcid: 4789491
doi: 10.1161/HYPERTENSIONAHA.115.06925
Kelly, T. N. et al. Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci. Hypertension 62, 853–9 (2013).
pubmed: 24001895
pmcid: 3972802
doi: 10.1161/HYPERTENSIONAHA.113.01148
Li, X. et al. Common polymorphism rs11191548 near the CYP17A1 gene is associated with hypertension and systolic blood pressure in the Han Chinese population. Am J Hypertens 26, 465–72 (2013).
pubmed: 23467202
doi: 10.1093/ajh/hps066
Levy, D. et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 41, 677–87 (2009).
pubmed: 19430479
pmcid: 2998712
doi: 10.1038/ng.384
Lin, Y. et al. Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China. Atherosclerosis 219, 709–14 (2011).
pubmed: 21963141
doi: 10.1016/j.atherosclerosis.2011.09.006
Yang, S. J. et al. Genetic variation in CYP17A1 is associated with arterial stiffness in diabetic subjects. Exp Diabetes Res 2012, 827172 (2012).
pubmed: 23133444
pmcid: 3485973
doi: 10.1155/2012/827172
Dai, C. F. et al. Haplotype analyses of CYP17A1 genetic polymorphisms and coronary artery disease in a Uygur population. J Renin Angiotensin Aldosterone Syst 16, 389–98 (2015).
pubmed: 25592814
doi: 10.1177/1470320314565840
Dai, C. F. et al. Relationship between CYP17A1 genetic polymorphism and coronary artery disease in a Chinese Han population. Lipids Health Dis 14, 16 (2015).
pubmed: 25889125
pmcid: 4359393
doi: 10.1186/s12944-015-0007-4
Bair, S. R. & Mellon, S. H. Deletion of the mouse P450c17 gene causes early embryonic lethality. Mol Cell Biol 24, 5383–90 (2004).
pubmed: 15169901
pmcid: 419874
doi: 10.1128/MCB.24.12.5383-5390.2004
Carvalho, L. C. et al. Clinical, hormonal, ovarian, and genetic aspects of 46,XX patients with congenital adrenal hyperplasia due to CYP17A1 defects. Fertil Steril 105, 1612–9 (2016).
pubmed: 26920256
doi: 10.1016/j.fertnstert.2016.02.008
Bianchi, P. H. et al. Successful Live Birth in a Woman With 17alpha-Hydroxylase Deficiency Through IVF Frozen-Thawed Embryo Transfer. J Clin Endocrinol Metab 101, 345–8 (2016).
pubmed: 26647153
doi: 10.1210/jc.2015-3201
Pencina, M. J. et al. Quantifying Importance of Major Risk Factors for Coronary Heart Disease. Circulation 139, 1603–1611 (2019).
pubmed: 30586759
doi: 10.1161/CIRCULATIONAHA.117.031855
Brown, J. C., Gerhardt, T. E. & Kwon, E. Risk Factors For Coronary Artery Disease. In StatPearls (Treasure Island (FL), 2020).
Njolstad, I., Arnesen, E. & Lund-Larsen, P. G. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 93, 450–6 (1996).
pubmed: 8565161
doi: 10.1161/01.CIR.93.3.450
Kaufman, J. M. & Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26, 833–76 (2005).
pubmed: 15901667
doi: 10.1210/er.2004-0013
Khaw, K. T. et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 116, 2694–701 (2007).
pubmed: 18040028
doi: 10.1161/CIRCULATIONAHA.107.719005
Steinfeld, K. et al. Low testosterone in ApoE/LDL receptor double-knockout mice is associated with rarefied testicular capillaries together with fewer and smaller Leydig cells. Sci Rep 8, 5424 (2018).
pubmed: 29615651
pmcid: 5882941
doi: 10.1038/s41598-018-23631-9
Bourghardt, J. et al. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology 151, 5428–37 (2010).
pubmed: 20861231
doi: 10.1210/en.2010-0663
Tivesten, A., Pinthus, J. H., Clarke, N., Duivenvoorden, W. & Nilsson, J. Cardiovascular risk with androgen deprivation therapy for prostate cancer: potential mechanisms. Urol Oncol 33, 464–75 (2015).
pubmed: 26141678
doi: 10.1016/j.urolonc.2015.05.030
Mesalic, L., Tupkovic, E., Kendic, S. & Balic, D. Correlation between hormonal and lipid status in women in menopause. Bosn J Basic Med Sci 8, 188–92 (2008).
pubmed: 18498273
pmcid: 5698353
doi: 10.17305/bjbms.2008.2980
Wing, R. R., Matthews, K. A., Kuller, L. H., Meilahn, E. N. & Plantinga, P. L. Weight gain at the time of menopause. Arch Intern Med 151, 97–102 (1991).
pubmed: 1985614
doi: 10.1001/archinte.1991.00400010111016
Zamboni, M. et al. Body fat distribution in pre- and post-menopausal women: metabolic and anthropometric variables and their inter-relationships. Int J Obes Relat Metab Disord 16, 495–504 (1992).
pubmed: 1323546
Torpy, J. M., Burke, A. E. & Glass, R. M. JAMA patient page. Coronary heart disease risk factors. JAMA 302, 2388 (2009).
pubmed: 19952328
doi: 10.1001/jama.302.21.2388
Elhage, R. et al. 17 beta-estradiol prevents fatty streak formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 17, 2679–84 (1997).
pubmed: 9409242
doi: 10.1161/01.ATV.17.11.2679
Villablanca, A., Lubahn, D., Shelby, L., Lloyd, K. & Barthold, S. Susceptibility to early atherosclerosis in male mice is mediated by estrogen receptor alpha. Arterioscler Thromb Vasc Biol 24, 1055–61 (2004).
pubmed: 15117737
doi: 10.1161/01.ATV.0000130467.65290.d4
Villablanca, A. C. et al. 17beta-estradiol prevents early-stage atherosclerosis in estrogen receptor-alpha deficient female mice. J Cardiovasc Transl Res 2, 289–99 (2009).
pubmed: 19654889
pmcid: 2719738
doi: 10.1007/s12265-009-9103-z
Nilsson, M. E. et al. Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry. Endocrinology 156, 2492–502 (2015).
pubmed: 25856427
doi: 10.1210/en.2014-1890
Stubbins, R. E., Holcomb, V. B., Hong, J. & Nunez, N. P. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr 51, 861–70 (2012).
pubmed: 22042005
doi: 10.1007/s00394-011-0266-4
Bismuth, J., Lin, P., Yao, Q. & Chen, C. Ceramide: a common pathway for atherosclerosis? Atherosclerosis 196, 497–504 (2008).
pubmed: 17963772
doi: 10.1016/j.atherosclerosis.2007.09.018
Ichi, I. et al. Association of ceramides in human plasma with risk factors of atherosclerosis. Lipids 41, 859–63 (2006).
pubmed: 17152923
doi: 10.1007/s11745-006-5041-6
Okutsu, M. et al. Corticosterone accelerates atherosclerosis in the apolipoprotein E-deficient mouse. Atherosclerosis 232, 414–9 (2014).
pubmed: 24468157
doi: 10.1016/j.atherosclerosis.2013.11.076