Sex difference on salt sensitivity and effects of estrogen deficiency on ischemic brain damage through water-free sodium accumulation

• Project/Area Number: 24592132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: 独立行政法人国立病院機構四国こどもとおとなの医療センター(臨床研究部(成育)、臨床研究部(循環器)) (2013-2014); The University of Tokushima (2012)
• Principal Investigator: KANEMATSU Yasuhisa 独立行政法人国立病院機構四国こどもとおとなの医療センター(臨床研究部(成育)、臨, その他部局等, その他 (90363142)
• Co-Investigator(Kenkyū-buntansha): NAGAHIRO Shinji 徳島大学, 大学院ヘルスバイオサイエンス研究部, 教授 (60145315) ; SATOMI Junichiro 徳島大学, 大学院ヘルスバイオサイエンス研究部, 准教授 (10304510)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脳虚血性疾患 / エストロゲン / 高塩分食 / 組織内Ｎａ貯留 / 組織内Na貯留 / 脳虚血 / 脳・神経 / 脳神経疾患 / 塩分貯留 / 性差

Outline of Final Research Achievements

Estrogen deficiency and hypertension are risk factors for stroke. In ovariectomized (OVX+) rats fed a high-salt diet (HSD), an increase in the body Na+/water ratio was associated with detrimental vascular effects. We hypothesized that an increase in brain water-free Na+ accumulation is associated with ischemic brain damage. The brain Na+/water ratio was increased in OVX+/normal diet (ND) rats as well as in OVX-/HSD and male rats fed HSD. It was augmented in OVX+/HSD rats. Importantly, the increased brain Na+/water ratio before ischemia was positively correlated with the expansion of cortical infarct. Neither OVX+ nor HSD affected the BP in female rats, while HSD increased BP in male rats. Our findings show that an increase in the brain Na+/water ratio elicited by HSD or estrogen deficiency is associated with ischemic brain damage, suggesting the importance of regulating the accumulation of brain water-free Na+

Research Products

• [Journal Article] Improvement of plasma biomarkers including angiotensin-(1-7) after switching from other angiotensin II type I receptor blockers to olmesartan in stroke patients with insufficient blood pressure control (2015)
  • Author(s): Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi, J, Kitazato, K, Kageji T, Matsuura E, Nagahiro S
  • Journal Title: J stroke cerebrovasc dis Volume: in press
  • Peer Reviewed
• [Journal Article] Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice (2015)
  • Author(s): Tada Y, Shimada K, Furukawa H, Wada K, Wei Y, Tada Y, Kuwabara A, Shikata F, Kanematsu Y, Lawton MT, Kitazato KT, Nagahiro S, Hashimoto T
  • Journal Title: J Cereb Blood Flow Metab Volume: Epub
  • Peer Reviewed
• [Journal Article] Estrogen protects against intracranial aneurysm rupture in ovariectomized mice (2014)
  • Author(s): Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Shikata F, Pena Silva RA, Kitazato KT, Hasan DM, Kanematsu Y, Nagahiro S, Hashimoto T
  • Journal Title: Hypertension Volume: 63 Pages: 1339-1344
  • Peer Reviewed
• [Journal Article] Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. (2014)
  • Author(s): Tada Y et al
  • Journal Title: Hypertension Volume: in press
  • Peer Reviewed
• [Journal Article] Role of hypertension in the rupture of intracranial aneurysms. (2014)
  • Author(s): Tada Y et al
  • Journal Title: Stroke Volume: 45 Pages: 579-586
  • Peer Reviewed
• [Presentation] Role of Angiotensin-(1-7) on intracranial aneurysm rupture (2014)
  • Author(s): Shimada K, K.Wada, H.Furukawa, Y.Wei, Y.Tada, A.Kuwabara, F.Shikata, K.T.Kitazato, S.Nagahiro, T.Hashimoto
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Role of angiotensin (1-7) and angiotensin type 2 receptor on intracranial aneurysmal rupture (2014)
  • Author(s): Shimada et al.
  • Organizer: International stroke conference 2014
  • Place of Presentation: San Diego, USA
• [Presentation] Suppression of High-mobility Group Protein Box-1 Signaling by Eicosapentaenoic Acid Ameliorates Brain Ischemic Damage in Oophorectomized Rats (2013)
  • Author(s): Sumiyoshi M et al
  • Organizer: ISC 2013
  • Place of Presentation: San Francisco, USA
• [Presentation] Down-regulation Of Vascular Na+/k+ ATPase In Oophorectomized Rats Feeding A High Salt Diet Is Associated With The Cerebral Aneurysm Formation (2013)
  • Author(s): Matsushita N et al
  • Organizer: ISC 2013
  • Place of Presentation: San Francisco, USA
• [Presentation] Suppression of High-mobility Group Protein Box-1 Signaling by Eicosapentaenoic Acid Ameliorates Brain Ischemic Damage in Oophorectomized Rats (2013)
  • Author(s): M.Sumiyoshi, et al.
  • Organizer: International STROKE Conference 2013
  • Place of Presentation: ヒルトンハワイアンビレッジ（アメリカ合衆国）