2025-08-22 九州大学
図1 重篤な感染症により生じるcytopathic hypoxiaの分子機序とHIF-1αの役割
<関連情報>
- https://www.kyushu-u.ac.jp/ja/researches/view/1319
- https://www.kyushu-u.ac.jp/f/63020/25_0822_01.pdf
- https://www.nature.com/articles/s44161-025-00687-1
リン脂質代謝によって過剰に誘導されたHIF-1αは、細胞病原性低酸素症を通じて敗血症性心筋症を引き起こす Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia
Masatsugu Watanabe,Masataka Ikeda,Ko Abe,Shun Furusawa,Kosei Ishimaru,Takuya Kanamura,Satoshi Fujita,Hiroko Deguchi Miyamoto,Eisho Kozakura,Yoko Shojima Isayama,Yuki Ikeda,Takashi Kai,Toru Hashimoto,Shouji Matsushima,Tomomi Ide,Ken-ichi Yamada,Hiroyuki Tsutsui,Ken Yamaura & Kohtaro Abe
Nature Cardiovascular Research Published:19 August 2025
DOI:https://doi.org/10.1038/s44161-025-00687-1
Abstract
Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.
