Piezo1 in Lupus Associated Cardiovascular Disease and Cognitive Impairment

People with systemic lupus erythematosus (SLE) often face complications involving the cardiovascular system, including hypertension, heart disease, and vascular inflammation (inflammation of the blood vessels), which significantly increases their risk of cardiovascular events. SLE can also affect the central nervous system, leading to neuropsychiatric SLE (NPSLE), which is linked to cognitive dysfunction and cerebrovascular disease. These complications highlight the critical need to understand the mechanisms behind SLE and its impact on cardiovascular and brain health. Recent studies have identified a protein called Piezo1 as crucial for cardiovascular health. Piezo1 helps cells sense and respond to mechanical forces, playing a key role in blood pressure regulation and immune responses.

Dr. Van Beusecum will investigate how dysregulation of Piezo1 signaling affects cardiovascular and brain health in SLE. He will study the effects of altering Piezo1 signaling (a communication network of proteins) in lupus-prone mice, focusing on how it impacts blood pressure, heart function, and cognition. He will use specific activators and inhibitors of Piezo1 to see how these changes influence disease outcomes like cognitive decline and memory deficits. Dr. Van Beusecum will then explore how mechanical stress on blood vessels influences Piezo1 signaling in heart and brain endothelial cells (cells that line the interior surface of blood vessels). This will involve detailed studies using RNA sequencing and advanced imaging techniques to understand how levels of Piezo1 change in heart and brain cells upon mechanical stimulation (applying physical forces, like stretching or pressure) and contribute to endothelial cell function and inflammation in SLE.

What this means for people with lupus

Dr. Van Beusecum’s research could provide new insights into how SLE affects the cardiovascular and nervous systems, potentially leading to new therapeutic targets. By understanding the role of Piezo1 in SLE-related complications, this study aims to facilitate the development of novel treatments that could improve cardiovascular and brain health in lupus patients, ultimately reducing their risk of severe complications and improving their quality of life.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately nine females to every male worldwide. Patients with SLE have a 7-9 fold higher incidence of cardiovascular disease (CVD). A common co-morbidity that affects patients with SLE associated CVD (SLE-CVD) is the pathological manifestations of SLE with involvement of the brain, termed neuropsychiatric SLE (NPSLE). Approximately 40-65% of patients with SLE have anxiety or mood disorders, and up to 80% have cognitive impairment. One common feature between SLE -CVD and NPSLE is the endothelial cell activation, dysfunction and inflammation. Mechanical forces act on the endothelium to promote endothelial cell activation and dysfunction in numerous disease states. Endothelial cells sense these forces through Piezo1, a mechanically activated cation channel, has been identified as critically important for endothelial and vascular function and dysfunction in numerous pathological conditions including cardiovascular disease, stroke, and hypertension. Based on our preliminary data, we propose that temporal dysregulation of Piezo1-mediated signaling promotes cardiac and cerebral endothelial dysfunction and the development of SLE-CVD and its associated cognitive impairment. In Aim 1 we will test the hypothesis that temporal dysregulation of cardio and neurovascular Piezo1 signaling promotes the development of SLE-CVD and its associated cognitive impairment. We will use female and male SLE-prone B6. Nba2 mice that develop NPSLE subjected to toll-like receptor 7/8 agonist to accelerate SLE development. We will examine Piezo1 signaling by treating mice with the Piezo1 activator, Yoda-1, or an inhibitor, Gsmtx-4 and assess in vivo blood pressure, cardiac and vascular physiology, and neurobehavior. We will also assess end-organ inflammation and damage by molecular biology and histological analysis. We predict that activation of Piezo1 will prevent the development of SLE-CVD and its associated cognitive impairment. In Aim 2, we will test the hypothesis that endothelial stretch and/or shear stress promotes pathological endothelial activation through a Piezo-1 dependent mechanism in SLE-CVD. We study primary female and male cardiac and brain endothelial cells from B6.Nba2 mice. We will assess Piezo-1dependent signaling using Yoda-1 and Gsmtx-4 under mechanical stimulation by RNA sequencing, Piezo1 channel electrophysiology and live cell confocal microscopy. We predict that activation of cardiac and brain endothelial cells will prevent endothelial cell activation and increase nitric oxide production. These studies will provide innovative targets and new therapeutic directions for the treatment of patients with SLE and NPSLE.