Sunday, May 18, 2025
5/18/2025
Role of Toll-Like Receptor Signaling in Cardiac Ischemia - Cardiovascular disease (CVD) is the number one killer in the United States. Every year about 735,000 Americans have a heart attack (myocardial ischemic injury). Of these, 525,000 are a first heart attack and 210,000 happen in people who have already had a heart attack. Cardiovascular endothelial dysfunction contributes to myocardial ischemic injury. Endothelial cells express pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). PPRs recognize pathogen associated molecular patterns (PAMPs) and endogenous (danger associated molecular patterns) ligands and initiate innate immune and inflammatory responses which promote immune cell infiltration into the myocardium. Recent evidence suggests that infiltrating macrophages and resident macrophages may have differential functions in mediating cardiac injury or cardiac repair following myocardial infarction (MI). Therefore, cardiac macrophage function may be critical for preservation of endothelial cell function, reducing myocardial ischemic injury and promoting repair of damaged heart tissue. During the last grant period, we have made a novel and exciting observation that endothelial cell specific heat shock protein A12B (HSPA12B) is an important mediator of crosstalk between endothelial cells and macrophages during MI. HSPA12B is a newly discovered member of the HSP70 family. It is predominantly expressed in endothelial cells, and plays an important role in the induction of angiogenesis by activation of phosphoinositide-3 kinase (PI3K)/Akt signaling. In our preliminary studies, we have discovered a novel role for HSPA12B in the regulation of macrophage function and angiogenesis during MI. Specifically, we found that endothelial cell specific HSPA12B deficiency (HSPA12B-/-) results in cardiac rupture which is associated with increased infiltrating macrophages and reduced resident macrophages in the myocardium during early phase of MI. In the late phase of MI, HSPA12B-/- mice exhibit worsened cardiac dysfunction and impaired cardiac angiogenesis. In contrast, transgenic mice which overexpress endothelial HSPA12B show significantly improved cardiac function and angiogenesis following MI. Thus, our findings indicate that endogenous endothelial cell HSPA12B exerts protection against myocardial ischemic injury. Importantly, we have discovered that HSPA12B is released from endothelial cells in exosomes that are uptaken by macrophages where it regulates macrophage phenotypes, thus reducing inflammatory responses. In addition, HSPA12B translocates into the nucleus accompanied by YAP/TAZ in endothelial cells and promotes angiogenesis. YAP/TAZ are two important co-effectors in Hippo signaling and they play an important role in the regulation of cell proliferation and angiogenesis. When taken together, our findings indicate that endothelial HSPA12B plays an important role not only in endothelial cell proliferation and angiogenesis but also in macrophage phenotypes during MI. Our preliminary data also suggests that endothelial HSPA12B may mediate crosstalk between endothelial cells and macrophages for repairing damaged heart tissue following MI. This application is focused on deciphering the cellular and molecular mechanisms by which endothelial HSPA12B differentially regulates macrophage phenotype and endothelial cell function during myocardial ischemic injury. Based on the preliminary data, we hypothesize that “endothelial HSPA12B is a novel effector for the protection against myocardial ischemic injury by differentially regulating macrophage phenotype and endothelial cell function”. To critically evaluate this hypothesis, we propose the following specific aims. Specific aim 1. Define the mechanisms by which endothelial HSPA12B regulates the function of infiltrating and resident macrophages during MI. Specific aim 2. Investigate the novel mechanisms by which HSPA12B regulates cardiac repair and angiogenesis following MI. Specific aim 3. Evaluate the therapeutic potential
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).