Excessive hypoxia-inducible factor-1α expression induces cardiac rupture via p53-dependent apoptosis after myocardial infarction

Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Midori Sato, Ko Abe, Shun Furusawa, Kosei Ishimaru, Shouji Matsushima, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿学術誌査読

19 被引用数 (Scopus)


BACKGROUND: Apoptosis plays a pivotal role in cardiac rupture after myocardial infarction (MI), and p53 is a key molecule in apoptosis during cardiac rupture. Hif-1α (hypoxia-inducible factor-1α), upregulated under hypoxia, is a known p53 inducer. However, the role of Hif-1α in the regulatory mechanisms underlying p53 upregulation, apoptosis, and cardiac rupture after MI is unclear. METHODS AND RESULTS: We induced MI in mice by ligating the left anterior descending artery. Hif-1α and p53 expressions were upregulated in the border zone at day 5 after MI, accompanied by apoptosis. In rat neonatal cardiomyocytes, treatment with cobalt chloride (500 μmol/L), which mimics severe hypoxia by inhibiting PHD (prolyl hydroxylase domain-containing protein), increased Hif-1α and p53, accompanied by myocyte death with caspase-3 cleavage. Silencing Hif-1α or p53 inhibited caspase-3 cleavage, and completely prevented myocyte death under PHD inhibition. In cardiac-specific Hif-1α hetero-knockout mice, expression of p53 and cleavage of caspase-3 and poly (ADP-ribose) polymerase were reduced, and apoptosis was suppressed on day 5. Furthermore, the cleavage of caspase-8 and IL-1β (interleukin-1β) was also suppressed in hetero knockout mice, accompanied by reduced macrophage infiltration and matrix metalloproteinase/tissue inhibitor of metalloproteinase activation. Although there was no intergroup difference in infarct size, the cardiac rupture and survival rates were significantly improved in the hetero knockout mice until day 10 after MI. CONCLUSIONS: Hif-1α plays a pivotal role in apoptosis, inflammation, and cardiac rupture after MI, in which p53 is a critical mediator, and may be a prospective therapeutic target for preventing cardiac rupture.

ジャーナルJournal of the American Heart Association
出版ステータス出版済み - 9月 7 2021

!!!All Science Journal Classification (ASJC) codes

  • 循環器および心血管医学


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