Loss of Endothelial Hypoxia Inducible Factor-Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis.

Abstract

Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α-dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

• Authors: Zhiyu Dai, Jianding Cheng, Bin Liu, Dan Yi, Anlin Feng, Ting Wang, Lingling An, Chen Gao, Yibin Wang, Maggie M Zhu, Xianming Zhang, You-Yang Zhao
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 10 Issue 22 Pg. e022077 (11 16 2021) ISSN: 2047-9980 [Electronic] England
• PMID: 34743552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Prolyl Hydroxylases
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Cardiomegaly (genetics, pathology)
• Endothelial Cells (pathology)
• Fibrosis
• Heart Failure (genetics, pathology)
• Humans
• Hypertrophy, Left Ventricular (pathology)
• Hypoxia (pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics)
• Mice
• Prolyl Hydroxylases