Watanabe Masatsugu, Ikeda Masataka, Abe Ko, Furusawa Shun, Ishimaru Kosei, Kanamura Takuya, Fujita Satoshi, Miyamoto Hiroko Deguchi, Kozakura Eisho, Isayama Yoko Shojima, Ikeda Yuki, Kai Takashi, Hashimoto Toru, Matsushima Shouji, Ide Tomomi, Yamada Ken-Ichi, Tsutsui Hiroyuki, Yamaura Ken, Abe Kohtaro
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nat Cardiovasc Res. 2025 Aug 19. doi: 10.1038/s44161-025-00687-1.
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.
脓毒症性心肌病是多器官功能障碍综合征的一种表现，是脓毒症中具有挑战性的并发症，细胞病变性缺氧被认为在多器官功能障碍综合征的病理生理学中起关键作用。然而，其潜在机制仍不清楚。在此，我们表明，脂多糖（LPS）处理后心肌细胞中缺氧诱导因子-1α（HIF-1α）的上调通过诱导型一氧化氮合酶依赖性一氧化氮抑制线粒体呼吸，导致细胞病变性缺氧。在脓毒症性心肌病小鼠模型中，心脏特异性杂合缺失HIF-1α可改善线粒体和收缩功能障碍。从机制上讲，核因子-κB（NF-κB）介导的环氧合酶2（COX2）和分泌型磷脂酶A2（sPLA2）上调在LPS暴露后增强HIF-1α表达，而抑制它们可防止LPS诱导的HIF-1α上调、细胞病变性缺氧和收缩功能障碍。此外，磷脂代谢产物（分别为前列腺素和溶血磷脂/游离脂肪酸）通过蛋白激酶A激活使HIF-1α稳定。这些发现突出了由LPS增强的磷脂代谢驱动的过量HIF-1α在脓毒症性心肌病中通过诱导细胞病变性缺氧所起的关键作用。
