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2019年03月27日

A novel role of tetrahydrobiopterin in cardiovascular system

日 時 2019年03月27日(水) 15:00 より 16:00 まで
講演者 Hyoung Kyu Kim,Associate professor
講演者所属 Cardiovascular and Metabolic Disease Center (CMDC). Inje University
場 所 山手地区 3号館2階西 共通セミナー室
お問い合わせ先 西田基宏
自然科学研究機構生命創成探究センター(生理学研究所)
心循環シグナル研究部門・教授
TEL&FAX: 0564-59-5560
要旨

Diabetic cardiomyopathy (DCM) is a major cause of mortality and morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous target in the cardiovascular system, its effect on myocardial cells and mitochondria in DCM and the underlying mechanism are unknown.
We tested whether BH4 deficiency is involved in DCM and if supplementation restores mitochondrial and heart function in late-stage DCM. The transcription of three BH4 synthesis-regulating genes was compared in cardiac tissues of patients with low or normal ejection fractions (EFs).
Forty-eight-week-old type 2 diabetic rats were divided into BH4 treatment and control groups. BH4 levels and the functions of heart and mitochondria were assessed in diabetic or control rats. Sepiapterin reductase knockout (Spr-/-) mice, a model of BH4 deficiency, were used to determine the mechanism of the therapeutic effect of BH4 on DCM.
Relative to control rats, diabetic rats, as well as Spr-/- mice, had cardiac contractility, hypertrophic remodeling, and mitochondrial dysfunction, which recovered with BH4 supplementation. BH4 directly bound to CaMKK2 and activated downstream pathways in cardiomyocytes.
BH4 is a novel therapeutic target for recovering the left ventricular contractility and structural remodeling in DCM via direct binding and activation of CaMKK2 signaling pathways.