Prohibitin-1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis.
Prohibitin-1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis.
复制标题
Prohibitin-1是一种动态调节的血液蛋白，在脓毒症中具有心脏保护作用。
DOI：
10.1161/jaha.120.019877
复制
发表时间：
2021-07-20
影响因子：
5.4
通讯作者：
Anderson EJ
中科院分区：
文献类型：
--
作者：
Mattox TA;Psaltis C;Weihbrecht K;Robidoux J;Kilburg-Basnyat B;Murphy MP;Gowdy KM;Anderson EJ
In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown. Using a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT signaling in the heart. These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.
