Abstract 12629: Endothelial Prolyl-4 hydroxylase 2 Deletion Induces Cardiac Hypertrophy and Heart Failure via Hypoxia Inducible Factor-2α Activation
Background: Cardiac hypertrophy is a common adaptive response to injury and stress, and can eventually lead to heart failure. The role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure is unclear. We hypothesize that endothelial PHD2/HIF signaling dysfunction contributes to cardiac hypertrophy and heart failure.
Methods: Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) (Egln1Tie2-Cre), as well as double knockout mice with both Egln1 and Hif1a or Egln1 and Hif2a were generated. Egln1f/f bone marrow cells were transplanted to lethally irradiated Egln1Tie2-Cre mice to determine the contribution of bone marrow cells in cardiac hypertrophy. Mice carrying Egln1f/f were bred into EndoSCL-Cre-ER(T) mice containing tamoxifen-inducible Cre to generate mice with Egln1 deletion only in endothelial cells in adult mice (Egln1SCL-Cre) after tamoxifen injection. Echocardiography were measured to study cardiac size and function. Histological examination was also performed.
Results: Egln1Tie2-Cre mice exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Egln1 deletion in bone marrow cells did not contribute to cardiac hypertrophy. Tamoxifen induced endothelial Egln1 deletion in adult Egln1SCL-Cre mice also induced left ventricular hypertrophy and heart failure. Genetic ablation of Hif2a but not Hif1a in Egln1Tie2 mice normalized cardiac size and function. Additionally, we observed a marked decrease of PHD2 expression in heart tissues from patients with dilated cardiomyopathy.
Conclusion: This studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and heart failure in a HIF-2α dependent manner. Thus, targeting PHD2/HIF-2α signaling represents a novel therapeutic approach for the treatment of heart failure.
Author Disclosures: Z. Dai: None. M. Zhu: None. C. Gao: None. X. Zhang: None. Y. Zhao: None.
- © 2016 by American Heart Association, Inc.