RRC ID 77505
Author Sasaki T, Kuse Y, Nakamura S, Shimazawa M.
Title Progranulin-deficient macrophages cause cardiotoxicity under hypoxic conditions.
Journal Biochem Biophys Res Commun
Abstract Myocardial infarction (MI) induces structural and electrical cardiac remodeling in response to ischemic insult, causing lethal arrhythmias and sudden death. Progranulin (PGRN) is a glycoprotein mainly expressed in macrophages that modulates the immune responses. In this study, we investigated the direct influence of PGRN knockout (Grn-/-) macrophages on post-MI pathophysiology. An MI mouse model was established by ligating the left coronary artery for RNA sequencing and electrocardiographic analysis. Bone marrow-derived macrophages (BMDMs) were injected into mice and supernatant was collected for the measurement of reactive oxygen species (ROS) levels and extracellular flux analysis. Administration of Grn-/- BMDMs prolonged the QT intervals in the MI mouse model. Moreover, genes highly expressed in macrophages were upregulated in Grn-/- heart after MI. Post-hypoxic supernatant of Grn-/- BMDMs increased the oxygen-glucose deprivation-induced cardiomyocyte death. Grn-/- BMDMs exhibited increased ROS production, oxygen consumption, and extracellular acidification under hypoxia and inflammatory conditions. These findings suggest that PGRN deficiency causes cardiotoxicity via secretory components of macrophages that exhibit metabolic abnormalities under hypoxia.
Volume 691
Pages 149341
Published 2023-11-28
DOI 10.1016/j.bbrc.2023.149341
PII S0006-291X(23)01435-3
PMID 38039836
IF 2.985
Mice RBRC02370