Year: 2025
Type: article
Abstract: Sepsis-induced cardiac dysfunction is a major contributor to sepsis-related mortality, and many patients continue to experience long-term cardiac complications after recovery. Here, we demonstrate that cardiac senescence is a key feature of sepsis-associated cardiac dysfunction, with endothelial cells identified as the predominant senescent population in septic cardiac tissue. However, the pathogenic drivers of endothelial senescence in sepsis remain poorly characterized. Among potential mediators, we found that elevated levels of heme, a byproduct of hemolysis, strongly correlate with increased endothelial senescence and impaired cardiac function. Mechanistic studies revealed that heme acts as a novel ligand for STING, exacerbating bacterial infection-induced STING polymerization and activation, thereby promoting endothelial senescence. Notably, either STING inhibition or enhanced heme clearance via increased hemopexin expression significantly alleviated cardiac endothelial senescence and facilitated cardiac functional recovery in septic mice. These findings identify heme as a critical pathogenic driver of endothelial senescence and highlight heme clearance as a promising therapeutic strategy for mitigating sepsis-induced cardiac dysfunction.
Source: Cell Death and Disease
Authors: Tingting Li, Peilin Zhu, Jialing Wang, Tao Zhang, Joseph Adams, Fei Tu, Chloe Garbe, Xiaojin Zhang, Li Liu, Krishna Singh, David L. Williams, Chuanfu Li, Xiaohui Wang
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,990
Funders: U.S. Department of Health and Human Services, East Tennessee State University, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1446181332, G1551366101, G1561813837, Novel role of LSECs in hepatic immune and metabolic function during sepsis, G331405470, G3846397788, G5043091194, G5322895359, G5476635362, Training Innate Immunity: A new approach to the treatment of Sepsis, Role of endothelial cell senescence in age-related cardiomyopathy, Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis, Novel Role of Lactate in Sepsis Impaired Immune Function, Request for the Acquisition of a Vevo F2 Ultrasound Imaging System, Innate Immunity and Cardiovascular Function in Sepsis
OpenAlex ID: W4417524998