Molecular genetic analyses of the CYP11B2 gene in cardiovascular tissues

2011 Fiscal Year Final Research Report

• Project/Area Number: 21790889
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: Kanazawa University
• Principal Investigator: DEMURA Masashi 金沢大学, 医学系, 助教 (00507080)
• Project Period (FY): 2009 – 2011
• Keywords: アルドステロン / エピジェネティクス / DNAメチル化 / 組織特異的プロモーター / CYP11B2 / 核内受容体 / 心筋症 / 心肥大

Research Abstract

In addition to the primary effect of aldosterone to induce sodium and fluid retention, excess aldosterone has direct inflammatory and fibrotic effects contributing to target organ deterioration, leading to the development of vascular, renal, and cardiac inflammation ; fibrosis ; and hypertrophy. Although the adrenal gland is a major source of aldosterone, aldosterone production and levels of mRNA coding for CYP11B2 are induced in the ventricles during hypertrophy, and aldosterone synthesis from heart itself causes cardiac hypertrophy. We showed a role for DNA methylation in CYP11B2 gene repression and suggest an epigenomic mechanism may be causally linked with an increase in cardiac aldosterone production in the pathophysiology of the heart. Meanwhile, nuclear receptors(NGFIB, NURR1, NOR1, SF1) involved in aldosteronogenesis differentially employed multiple alternative promoters(APs) in a tissue-specific manner. The use of APs was different between human adrenal and cardiovascular tissues.

Research Products

• [Journal Article] Unilateral primary aldosteronism with spontaneous remission after long-term spironolactone therapy (2012)
  • Author(s): Yoneda T, Demura M, Takata H, KometaniM, Karashima S, Yamagishi M, Takeda Y.
  • Journal Title: J Clin Endocrinol Metab Volume: 97 Pages: 1109-13
  • DOI: doi:10.1210/jc.2011-2563
  • Peer Reviewed
• [Journal Article] Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats (2012)
  • Author(s): Takata H, Takeda Y, Zhu A, Cheng Y, Yoneda T, Demura M, Yagi K, Karashima S, Yamagishi M.
  • Journal Title: Diabetes Obes Metab Volume: 14 Pages: 155-62
  • DOI: doi:10.1111/j.1463-1326.2011.01499.x
  • Peer Reviewed
• [Journal Article] Changes in aromatase(CYP19) gene promoter usage in non-small cell lung cancer (2011)
  • Author(s): Demura M, Demura Y, Ameshima S, Ishizaki T, Sasaki M, Miyamori I, Yamagishi M, Takeda Y, Bulun SE.
  • Journal Title: Lung Cancer Volume: 73 Pages: 289-93
  • DOI: doi:10.1016/j.lungcan.2011.01.003
  • Peer Reviewed
• [Journal Article] Clinical characteristics of primary hyperaldosteronism due to adrenal microadenoma (2011)
  • Author(s): Karashima S, Takeda Y, Cheng Y, YonedaT, Demura M, Kometani M, Ohe M, Mori S, Yagi K, Yamagishi M.
  • Journal Title: Steroids Volume: 76 Pages: 1363-6
  • DOI: doi:10.1016/j.steroids.2011.07.004
  • Peer Reviewed
• [Journal Article] Multiple noncoding exons 1 of nuclear receptors NR4A family(nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derivedorphan receptor 1) and NR5A1(steroidogenic factor 1) in human cardiovascular and adrenal tissues (2011)
  • Author(s): Demura M, Wang F, Yoneda T, Karashima S, Mori S, Oe M, Kometani M, Sawamura T, Cheng Y, Maeda Y, Namiki M, Ino H, FujinoN, Uchiyama K, Tsubokawa T, Yamagishi M, Nakamura Y, Ono K, Sasano H, Demura Y, Takeda Y
  • Journal Title: J Hypertens Volume: 29 Pages: 1185-95
  • DOI: DOI:10.1097/HJH.0b013e32834626bb
  • Peer Reviewed
• [Journal Article] アルドステロン産生のエピジェネティクス (2010)
  • Author(s): 出村昌史、山岸正和、武田仁勇
  • Journal Title: 最新医学 Volume: 65巻(10) Pages: 71-78
• [Journal Article] A possible new syndrome with double endocrine tumors in association with an unprecedented type of familial heart-hand syndrome : a case report (2010)
  • Author(s): Demura M, Yoneda T, Karashima S, Higashikata T, Mabuchi H, Kawano M, Yamagishi M, Takeda Y.
  • Journal Title: J Med Case Reports Volume: 29 Pages: 347
  • DOI: doi:10.1186/1752-1947-4-347
  • Peer Reviewed
• [Journal Article] Ectopic production of parathyroid hormone in a patient with sporadic medullary thyroid cancer (2010)
  • Author(s): Demura M, Yoneda T, Wang F, Zen Y, Karashima S, Zhu A, Cheng Y, YamagishiM, Takeda Y.
  • Journal Title: Endocr J Volume: 57 Pages: 161-70
  • DOI: 10.1507/endocrj.K09E-131
  • Peer Reviewed
• [Journal Article] A Humanized Pattern of Aromatase Expression Is Associated with Mammary Hyperplasia in Mice
  • Author(s): Zhao H, Pearson EK, Brooks DC, Coon V JS, Chen D, Demura M, Zhang M, Clevenger CV, Xu X, Veenstra TD, Chatterton RT, Demayo FJ, Bulun SE.
  • Journal Title: Endocrinology Volume: (in press)
  • DOI: doi:10.1210/en.2011-1761
  • Peer Reviewed
• [Presentation] Multiple noncoding exons 1 of nuclear receptors NR4A family(NGFIB, NURR1, NOR1) and NR5A1(SF1) in human vascular and adrenal tissues (2011)
  • Author(s): Masashi Demura, Fen Wang, Takas Yoneda, Shigehiro Karashima, Shunsuke Mori, Mistuhiro Kometani, Masashi Oe, Yuan Cheng, Yuji Maeda, Mikio Namiki, Katsuhiko Ono, Yasuhiro Nakamura, Hironobu Sasano, Kiyofumi Saijoh, Yoshiyu Takeda
  • Organizer: The Endocrine Society's 93^<th> Annual Meeting, the Boston Convention & Exhibition Center
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 20110604-07
• [Presentation] Epigenomic alterations activate the CYP11B2(aldosterone synthase) gene in cardiomyopathy (2011)
  • Author(s): Fen Wang, Masashi Demura, Takashi Yoneda, Shunsuke Mori, Masashi Oe, Yuan Cheng, Hidekazu Ino, Noboru Fujino, Uchiyama Katsuharu, Toshinari Tsubokawa, Masakazu Yamagishi, Yasuhiro Nakamura, Katsuhiko Ono
  • Organizer: The 4^<th> International Aldosterone Forum in Japan
  • Place of Presentation: Grand Hall, Tokyo
  • Year and Date: 2011-05-14
• [Presentation] Epigenetic regulation of the (2010)
  • Author(s): Fen Wang, Masashi Demura, Takashi Yoneda, Shigehiro Karashima, Shunsuke Mori, Mistuhiro Kometani, Masashi Oe, Yuan Cheng, KatsuharuUchiyama, Chiaki Nakanishi, Toshinari Tsubokawa, Hidekazu Ino, Noboru Fujino, Masakazu Yamagishi, Yuji Maeda, Mikio Namiki, Yoshiyu Takeda
  • Organizer: aldosterone synthase CYP11B2 gene 23^<rd> Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Vancouver Convention Centre, Canada
  • Year and Date: 20100926-30
• [Presentation] Effect of DNA Methylation on Aldosterone Synthase Gene (2010)
  • Author(s): Masashi Demura, Fen Wang, Takashi Yoneda, Shigehiro Karashima, Shunsuke Mori, Mistuhiro Kometani, Masashi Oe, Yuan Cheng, Katsuharu Uchiyama, Masakazu Yamagishi, Yuji Maeda, Mikio Namiki, Yoshiyu Takeda
  • Organizer: The Endocrine Society's 92^<th> Annual Meeting, San Diego Convention Center
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 20100619-22
• [Presentation] Multiple noncoding first exons of nuclear receptors NR4A family(NGFIB, NURR1, NOR1) and NR5A1(SF1) in human adrenal and vascular tissues (2010)
  • Author(s): Masashi Demura, Fen Wang, Takashi Yoneda, Shigehiro Karashima, Shunsuke Mori, Mistuhiro Kometani, Masashi Oe, Yuan Cheng, Yuji Maeda, Mikio Namiki, Masakazu Yamagishi, Yoshiyu Takeda
  • Organizer: The 3^<rd> International Aldosterone Forum in Japan
  • Place of Presentation: Grand Hall, Tokyo
  • Year and Date: 20100515-16
• [Presentation] Epigenetics in aldosteroneproduction (2010)
  • Author(s): Masashi Demura, Fen Wang, Takashi Yoneda, Shigehiro Karashima, Shunsuke Mori, Mistuhiro Kometani, Masashi Oe, Yuan Cheng, Katsuharu Uchiyama, Chiaki Nakanishi, Toshinari Tsubokawa, Hidekazu Ino, Noboru Fujino, Masakazu Yamagishi, Yuji Maeda, Mikio Namiki,Yoshiyu Takeda
  • Organizer: International Symposium on Cardiovascular Endocrinology and Metabolism CVEM 2010
  • Place of Presentation: Nara Prefectural New Public Hall, Nara
  • Year and Date: 20100331-0401
• [Presentation] Epigenetic transcriptional repression of the human CYP11B2 gene (2010)
  • Author(s): Masashi Demura, Takashi Yoneda, Shigehiro Karashima, Fen Wang, Yuan Cheng, Masakazu Yamagishi, Yoshiyu Takeda
  • Organizer: The 14th International Congress of Endocrinology ICE 2010
  • Place of Presentation: 国立京都国際会館, Kyoto, Japan
  • Year and Date: 20100326-30
• [Presentation] Epigenetic regulation of aldosterone production (2010)
  • Author(s): Masashi Demura, Fen Wang, Takashi Yoneda, Shigehiro Karashima, Yuan Cheng, Yoshiyu Takeda
  • Organizer: International Symposium for Aldosterone and Related Substances in Hypertension(ISARSH 2010)
  • Place of Presentation: Hotel Metropolitan Sendai, Sendai, Japan
  • Year and Date: 20100323-24
• [Presentation] Regulation of the orphan nuclear receptor NR4A family by multiple promoters in the adrenocortical H295R cells (2009)
  • Author(s): Masashi Demura, Takashi Yoneda, Shigehiro Karashima, Aoshuang Zhu, Masakazu Yamagishi, Yoshiyu Takeda
  • Organizer: 19^<th> European Meeting on Hypertension ESH2009
  • Place of Presentation: Milan Convention Center, Milan, Italy
  • Year and Date: 20090612-16
• [Presentation] Epigenetic transcriptional repression of the CYP11B2 gene in human adrenocortical cells (2009)
  • Author(s): Masashi Demura, Takashi Yoneda, Shigehiro Karashima, Aoshuang Zhu, Masakazu Yamagishi, Yoshiyu Takeda
  • Organizer: The 2^<nd> International Aldosterone Forum in Japan
  • Place of Presentation: Grand Hall, Tokyo
  • Year and Date: 20090516-17
• [Remarks]
  • URL: http://www.aldosterone.jp/conference_report/090516/j04/index.php