Abstract 16855: Endothelial Dysfunction Through MAPK Signaling in Cardiac Hypertrophy and Failure

Abstract

Heart failure (HF) is the most frequent cause of hospitalization in people over 65 years. Endothelial dysfunction correlates with worse outcomes in HF, and although it has been observed in both preserved (HFpEF) and reduced (HFrEF) ejection fraction patient populations, it has been intensely studied predominantly in the latter group, due to challenges in diagnosis, limited human tissue samples and lack of animal models of HFpEF. Here, we present a novel mouse model of endothelial dysfunction caused by loss of the Mitogen Activated Protein Kinase (MAPK) Erk5, which develops cardiac hypertrophy and a HFpEF phenotype. Tamoxifen inducible endothelial specific deletion of Erk5 (Erk5 ECKO ) is lethal within 25 days. Serial echocardiograms showed that Erk5 ECKO mice develop dramatic left ventricle hypertrophy, characterized by increased heart/body weight ratios, increased cardiomyocyte size and extended fibrosis. The ejection fraction was remarkably preserved, while blood pressure was unaffected. Erk5 ECKO mice presented with increased expression of HF biomarkers and fibrotic genes, as well as increased proliferation of cardiac endothelial cells. Knockdown of ERK5 in endothelial cells resulted in dysregulation of multiple homeostatic genes, including decreased phosphorylation and subsequent degradation of YAP, a pro-proliferative Hippo pathway effector. Increased protein levels of Yap were identified both in Erk5 ECKO mouse hearts and in a subset of human HF left ventricle samples. Finally, using tamoxifen inducible, endothelial specific knockout mice of both Erk5 and Yap we show that endothelial loss of Yap improves left ventricle hypertrophy and normalizes HF biomarker expression in Erk5 ECKO mice. Our findings provide critical mechanistic knowledge on the role of endothelial dysfunction in HFpEF, downstream of impaired MAPK signaling, while setting forth new biomarkers and therapeutic candidates for diseases involving endothelial dysfunction.