Calcific aortic stenosis: Identification of calcification-inducing cell, clarifying calcification signaling

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10449
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Hirosaki University
• Principal Investigator: Seya Kazuhiko 弘前大学, 医学研究科, 助教 (40281919)
• Co-Investigator(Kenkyū-buntansha): 古川 賢一 弘前大学, 医学研究科, 准教授 (20165468) ; 福田 幾夫 弘前大学, 医学研究科, 教授 (50344594) ; 大徳 和之 弘前大学, 医学部附属病院, 准教授 (50374822) ; 村上 学 弘前大学, 医学研究科, 教授 (80302090)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 大動脈弁狭窄症 / 異所性石灰化 / 大動脈弁間質細胞 / マトリックスGlaタンパク質 / テネイシンX

Outline of Final Research Achievements

Initially, it was confirmed that many of aortic valve interstitial cells (HAVICs) obtained from the aortic valve had characteristics as mesenchymal undifferentiated cells (CD73, 90, 105 (+) / CD45 (-) cells). When hematopoietic stem cell markers, CD34 positive and negative cells were separated from these cells, it was found that CD34 negative cells were sensitive to various calcification stimulations. Microarray analysis of gene expression between CD34 negative and positive cells indicated that low expression of tenascin X (TNX) gene, one of the extracellular matrix proteins, may contribute to the calcification of HAVICs. On the other hand, we confirmed that knockdown of matrix Gla protein (MGP) which is a bone morphogenetic protein 2 antagonist induced spontaneous calcification of HAVICs. These results suggest that knockdown cells of extracellular matrix proteins, TNX and/or MGP, may become calcification-inducing cells in aortic valve.

Free Research Field

循環器薬理学

Academic Significance and Societal Importance of the Research Achievements

・本研究の学術的意義は、異所性石灰化について動脈硬化以外の要因を調べることであり、そのために弁内に存在する未分化細胞に着目して石灰化の原因細胞を明らかにするところにある。
・異所性石灰化機構の解明は、石灰化大動脈弁狭窄症の病態基盤を構築し、石灰化シグナリング機構を抑制する活性物質を礎とした新規薬物治療薬の開発に応用できると共に、高齢者の健康寿命向上に寄与することができることに社会的意義がある。