title: MICU1 may be a promising intervention target for gut-derived sepsis induced by intra-abdominal hypertension.
abstract: Intra-abdominal hypertension (IAH) is a common and serious complication in critically ill patients, for which there is no targeted therapy. IAH-induced dysfunction of intestinal barriers is closely associated with oxidative imbalances, which are considered to provide a pathophysiological basis for subsequent gut-derived sepsis. However, the upstream mechanism that produces oxidative damage during IAH remains unknown. It is not clear whether 'mitochondrial Ca2+uptake 1' (MICU1, the key protein regulating the oxidative process) is involved in preventing Ca2+m(mitochondrial Ca2+) overload. Here, we detected changes in the expression of MICU1 during the development of increased intestinal permeability in rats with IAH, and we explored the related mechanism regulating epithelial-barrier functions by knocking-downmicu1in Caco-2 cells. Our results demonstrated that, to combat IAH-induced dysfunction of intestinal barriers, MICU1 undergoes a compensatory increase in expression, whereas 'mitochondrial calcium uniporter' (MCU) - a conserved Ca2+transporter - becomes transcriptionally suppressed. Silencing the expression of MICU1 destroyed Caco-2 cell barrier integrity, promoted paracellular permeability, and impaired the expression of tight junction proteins (occludin, ZO-1, and claudin 1). Meanwhile, oxidative imbalances were induced; malondialdehyde (MDA), a product of oxidation, was increased and antioxidant products (GSH-Px, CAT, and SOD) were decreased. In MICU1-deficient Caco-2 cells, proliferation was inhibited and apoptosis was promoted. Collectively, our results indicate that MICU1-related oxidation/antioxidation disequilibrium is strongly involved in IAH-induced damage to intestinal barriers. MICU1-targeted treatment may hold promise for preventing the progression of IAH to gut-derived sepsis.
authors.affiliation: Department of Intensive Care Unit, Peking University Third Hospital , North Garden Road, No. 49, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Department of Intensive Care Unit, Peking University Third Hospital , North Garden Road, No. 49, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Ge
authors.affiliation: Department of Intensive Care Unit, Peking University Third Hospital , North Garden Road, No. 49, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Intensive Care Unit, Peking University Third Hospital , North Garden Road, No. 49, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Intensive Care Unit, Peking University Third Hospital , North Garden Road, No. 49, Haidian District, Beijing 100191, People's Republic of China.
authors.forename: Gaiqi
authors.initials: G
authors.lastname: Yao