Endothelial HSPA12B regulates myocardial monocyte infiltration and inflammatory activity after myocardial infarction

Kun Yang^1*Yana Wang²Min Fan¹Linjian Chen¹Patrick Spencer Gill³Xiaohui Wang¹Tuanzhu Ha¹David L Williams¹Chuanfu Li^1*

• ¹East Tennessee State University, Johnson City, United States
• ²First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
• ³Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NIH), Bethesda, Maryland, United States

Cardiac macrophages play an important role in both cardiac injury and repair processes after myocardial infarction (MI). The present study investigated the influence of endothelial cell specific heat shock protein A12B (eHSPA12B) on the regulation of cardiac macrophage infiltration and inflammatory response after MI. In vivo findings reveal that deficiency of eHspa12b markedly exacerbates cardiac dysfunction, accompanied with increased numbers of macrophages. In addition, the number of infiltrated monocyte was significantly higher in Hspa12b -/-hearts, when compared to WT hearts, 3 days post-MI induction. These data imply a potential regulatory role of eHSPA12B in macrophage infiltration and activation after MI. Endothelial cellconditioned medium from HSAP12B-overexpressed endothelial cells shifted macrophages from a pro-inflammatory to a pro-regenerative phenotype in response to hypoxia. Notably, HSPA12B protein is released via exosome secretion from endothelial cells. We found that HSPA12B-containing exosomes also promote a pro-regenerative macrophage phenotype. This phenotype was characterized by reduced proinflammatory cytokine production and increased anti-inflammatory cytokine secretion.Mechanistically, this effect was mediated by the degradation of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) in macrophages.Collectively, our study unveils a novel role of eHSPA12B in regulating macrophage infiltration and activation following MI.