Sex Differences in Temporal Regulation of Piezo1 in Resiquimod Accelerated Systemic Lupus

Abstract

Lupus disproportionally affects women (9:1), particularly women of color, but men with this disease often have more pronounced symptoms than their female counterparts. Individuals with lupus are anywhere from two to fifty times as likely to experience a cardiovascular (CV) event than the rest of the population. Though such complications are widely known, the mechanisms these disease processes are unknown. One well established pathogenesis of many CV diseases stems from an alteration of mechanical forces. The cation channel, Piezo1, is a mechanosensitive channel and is known to play a critical role in CV diseases like heart failure. Therefore, we hypothesized that inducing lupus-associated cardiac pathology in a lupus-prone mouse model would increase the expression of Piezo1. To investigate this, lupus-prone female and male B6.Nba2 mice aged 10-14 weeks were subjected to Resiquimod (R848; a TLR7/8 agonist;100μg/30μl) treatment or acetone vehicle twice a week for four weeks. Echocardiograms were performed every four weeks. Mice were sacrificed and their tissues harvested at 4- and 16-weeks after the start of R848 treatment. Piezo1 levels were subsequently analyzed in the heart by real time quantitative polymerase chain reaction (RTqPCR), immunoblot, and immunofluorescent staining. By echocardiography, female mice treated with R848 showed an increase in left ventricle (LV) wall thickness was seen at four weeks, followed by an increase in internal diameters over the following 12 weeks, culminating in cardiac dysfunction by 16 weeks via significantly decreased ejection fraction (EF; p<0.05) Interestingly, males showed no such cardiac dysfunction at any timepoint. By RTqPCR, female Piezo1 levels were higher overall than their male counterparts (p<0.05). Cardiac Piezo1 gene expression at 4 weeks was shown to be decreased in the R848-treated groups of both sexes. At 16 weeks, this trend was reversed in both male and female mice, showing R848-treatment induced an an upregulation of cardiac Piezo1 compared to each sex’s respective vehicle controls. Interestingly, while Piezo1 protein expression followed the same 4-week trend of downregulation in R848-treated mice regardless of sex, protein expression in the female R848-treated heart continued in a trending increase at the 16-week timepoint, while the male R848 heart showed unchanged. We found that this increase in cardiac Piezo1 in female, R848-treated is significantly correlated with higher left ventricular internal diameters (both LV-EDV (p<0.05) and -ESV (p<0.01)). This data demonstrates a sex difference phenotype in lupus-associated murine cardiac dysfunction, potentially through a Piezo1-mediated pathway. Further investigation is warranted to elucidate the Piezo1-dependent mechanisms involved in lupus-associated cardiovascular disease. Veterans Affairs Biomedical Laboratory Research & Development Career Development Award (CDA-2) 1IK2BX005605-01 to J.P.V.B, Medical University of South Carolina College of Medicine Program Project Grant to and J.P.V.B., and Medical University of South Carolina Core Centers for Clinical Research Project Award P30AR072582 to M.A.C and J.P.V.B. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.