Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

Dai, Z.; Cheng, J.; Liu, B.; Yi, D.; Feng, A.; Wang, T.; Gao, C.; Wang, Y.; Zhu, M. M.; Zhang, X.; Zhao, Y.

doi:10.1101/2021.03.19.434301

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bioRxiv · 10.1101/2021.03.19.434301

Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

Dai, Z.·Cheng, J.·Liu, B.·Yi, D.·Feng, A.·Wang, T.·Gao, C.·Wang, Y.·Zhu, M. M.·Zhang, X.·Zhao, Y.

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Abstract

BackgroundCardiac 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 Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. Methods and ResultsMice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) (Egln1Tie2Cre) exhibited left ventricular (LV) hypertrophy evident by increased thickness of anterior and posterior wall and LV mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced LV 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-2 as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2 attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. ConclusionsThe present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2 dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2 signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

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Dai, Z., Cheng, J., Liu, B., Yi, D., Feng, A., Wang, T., Gao, C., Wang, Y., Zhu, M. M., Zhang, X., Zhao, Y.. 2021-03-20. Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis. https://doi.org/10.1101/2021.03.19.434301

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