HEG1 as a regulator of hypertension and atherosclerosis

The National Heart, Lung, and Blood Institute awarded Emory University $315,700 on March 13, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate HEG1 as a regulator of hypertension and atherosclerosis. The project, identified as F32HL182251, runs through September 11, 2027, with place of performance in Atlanta, Georgia.

The research examines the role of heart of glass 1 (HEG1), a flow-sensitive gene, in endothelial cell dysfunction linked to both hypertension and atherosclerotic cardiovascular disease. The work will define cellular and physiologic mechanisms of HEG1-dependent hypertension and determine the role of secreted HEG1 in hypertension and atherosclerosis progression. The project also investigates whether secreted HEG1 could serve as a biomarker of endothelial dysfunction in cardiovascular disease patients. The research builds on prior findings showing that endothelial-cell-specific knockout of HEG1 in mice causes hypertension and accelerated atherosclerosis, and that reduced circulating HEG1 levels in humans associate with hypertension, dyslipidemia, and altered liver and kidney function. The assistance type is a project grant.

Abstract

Atherosclerotic cardiovascular disease (ascvd) is the leading cause of death worldwide. Hypertension (HTN) is the leading modifiable risk factor for death from ascvd. HTN is a mechanistically heterogenous disease with heterogenous treatment response and without robust biomarkers of disease control, complicating treatment and motivating US to understand the pathophysiology of HTN at the molecular, cellular, and physiologic levels. Mechanistically, endothelial cell (EC) dysfunction is linked to both HTN and atherosclerosis via multiple pathways. In the vasculature, stable blood flow (s-flow) drives healthy, atheroprotective EC functions (including nitric oxide / redox signaling, barrier function, and anti-inflammatory programs) via the action of flow-sensitive genes and proteins. Our lab has identified one such flow sensitive gene heart of glass 1 (HEG1) which plays a critical atheroprotective role regulating the activity of master transcription factors KLF2/4, and is also secreted from the cell in response to stable flow. Remarkably, we have shown that inducible, EC-specific knockout of HEG1 in mice causes hypertension and accelerated atherosclerosis relative to controls in a western diet and PCSK9 background. Other groups have shown that in human patients, reduced levels of circulating HEG1 in the blood are associated with multiple disease processes, including HTN, dyslipidemias, as well as altered liver and kidney function. The mechanisms underlying HEG1-dependent hypertension and atherosclerosis are elusive. Moreover, the role of secreted HEG1 (SHEG1) in HTN and atherosclerosis is completely unknown, and IT is unknown whether SHEG1 might drive ascvd, or potentially serve as a useful biomarker of EC dysfunction in US patients with cardiovascular disease. In aim 1 we will define the cellular and physiologic mechanisms of HEG1- dependent hypertension. We will determine the role of HEG1 in vascular reactivity and arterial stiffness employing in vivo and EX vivo approaches. We will determine the role of HEG1-dependent HTN in atherosclerosis progression using a pharmacologic approach in vivo. We will define the role of HEG1 in EC transcriptional reprogramming using scrna-SEQ in our inducible, EC-specific HEG1 knockout mouse (HEG1-iecko). In aim 2 we will determine the role of circulating HEG1 as a regulator or biomarker of EC function. We will perform cardiometabolic phenotyping of our HEG1-iecko mice, interrogating their cardiac, renal and hepatic function. We will determine whether secreted forms of HEG1 are sufficient to rescue the HEG1-iecko HTN and atherosclerotic phenotypes, and we will validate HEG1 as a potential biomarker for ascvd using patient specimens. Together, these aims will define novel mechanistic connections between EC function, HTN and atherosclerosis, laying the groundwork for novel therapies. Moreover, this proposal will allow me to develop expertise in cardiovascular research and build a strong foundation for an independent research career.