Endothelial FLI1 in ischemic heart disease

The National Heart, Lung, and Blood Institute (NHLBI) awarded The University of Texas Southwestern Medical Center $718,548 on July 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of endothelial FLI1 in ischemic heart disease.

The funded research examines how Friend Leukemia Integration 1 (FLI1), a transcription factor, governs endothelial cell function and protects against myocardial damage under ischemic stress. Preliminary data using tamoxifen-inducible endothelial cell-specific FLI1 knockout mice indicate that loss of endothelial FLI1 causes no overt phenotype under basal conditions but plays a protective role during ischemia, antagonizing myocardial damage and contractile dysfunction. In myocardial infarction hearts, endothelial FLI1 is essential for inducing endothelial KIT and neuregulin-1 (NRG1) expression, which promote communication with immune cells and cardiomyocytes, angiogenesis, and cardiomyocyte viability. The research employs a multidisciplinary strategy to determine endothelial FLI1 action in ischemic heart disease and delineate the role of FLI1-KIT-METRLN and FLI1-NRG1-ERBB2 axes in ischemia-induced myocardial injury.

The award is a Project Grant with a period of performance from July 1, 2026, through May 31, 2030. Work is performed at The University of Texas Southwestern Medical Center in Dallas, Texas.

Abstract

Friend leukemia integration 1 (FLI1) plays critical roles in vascular morphogenesis by regulating the endothelial potential of progenitors and expression of a wide range of genes involved in key molecular and cellular events, including responses to stress, cell growth, and viability during embryogenesis. However, the role and molecular mechanisms whereby FLI1 governs endothelial function after development are unknown. Preliminary data presented here utilizing tamoxifen-inducible endothelial cell (EC)-specific FLI1 knockout (FLI1-EKO) mice suggest that loss of endothelial FLI1 in isolation causes no overt phenotype under basal conditions. However, under conditions of ischemic stress, FLI1 is activated, playing a key, protective role to antagonize myocardial damage and contractile dysfunction. We have also noted that in myocardial infarction (MI) hearts, endothelial FLI1 is essential for marked induction of endothelial kit and neuregulin-1 (NRG1) expression which are essential for communication with immune cells and cardiomyocytes, promoting angiogenesis and cardiomyocyte viability, respectively. Based on these exciting preliminary data, we hypothesize that endothelial FLI1 is essential for cell-cell communication to antagonize ischemia-induced myocardial damage and heart failure. Here, we propose a multidisciplinary strategy of investigation to address this: aim 1: to determine and manipulate endothelial cell FLI1 action in ischemic heart disease. Aim 3: to delineate the role of a FLI1-kit-metrln axis in ischemia-induced myocardial injury. Aim 3: to delineate the role of a FLI1-NRG1-ERBB2 axis in ischemic heart. Recent insights into the molecular basis of a kit-metrln axis and NRG-1 in oxidative damage and growth of cardiomyocytes have raised the intriguing possibility that endothelial FLI1 situated at the nexus of endothelial- myocardial-immune cell communication is a molecule of novel therapeutic relevance. Whereas FLI1 is known to participate in endothelial cell growth and homeostasis, we have uncovered novel FLI1 actions in endothelium, governing communication with immune cells and cardiomyocyte health in ischemic heart, both of which we propose to elucidate here. In SUM, studies proposed here will define the mechanisms and functional relevance of endothelial FLI1 signaling in cardiac health and disease.