A novel murine model for endothelial dysfunction and heart failure with preserved ejection fraction

Abstract

The prevalence of Heart Failure with Preserved Ejection Fraction (HFpEF) is dramatically increasing and associated with high mortality. HFpEF predominantly affects elderly (> 65 years) hypertensive women with cardiovascular and non-cardiovascular comorbidities such as obesity, diabetes, atrial fibrillation or renal dysfunction. Mechanisms underlying HFpEF are poorly understood today. A new, but still untested paradigm, focusing on the role of endothelial cells (EC), has recently emerged. The ubiquitine ligase PDZRN3 is a component of the non-canonical Wnt pathway and its endothelial expression has been linked to vascular bed stability. Here, we investigated long-term consequences of endothelial PDZRN3 signaling activation, on heart failure. Investigate the etiology and functional consequence of EC dysfunction in HFpEF. We have generated mice which had post-natal restrictive and inducible endothelial expression of Pdzrn3 (iEC-Pdzrn3). EC specific Pdzrn3 overexpression was induced under tamoxifen administration to 5-week-old mice. To potentiate EC dysfunction, mice were fed with high fat diet for 3 months and studied at 6 months by echocardiography, histology and hemodynamic parameters. At 6 months, both iEC-Pdzrn3 female and male cohorts displayed hemodynamic parameters of HFpEF with a significant strong elevation of the end-diastolic pressure compared to their respective littermates (2.7-fold increase for females, P = 0.02, N = 10; and 1.5-fold increase for males, P = 0.04, N = 10) but did not show any other sign of echocardiography dysfunction. In both female and male cohorts, mutants presented low-grade of inflammation characterized by macrophages infiltration. Precocious times and histological parameters are currently under investigation. iEC-Pdzrn3 mice fed with high fat diet develop markers of HFpEF within 6 months of life.