Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia

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. Watanabe et al. show that cytopathic hypoxia, through upregulation of COX2 and secretory PLA2, stabilizes HIF-1α, contributing to impaired mitochondrial respiration and reduced cardiac contraction in septic cardiomyopathy.