Role of Hypoxia-Inducible Factors in Regulating Right Ventricular Function and Remodeling during Chronic Hypoxia-induced Pulmonary Hypertension.

American Journal of Respiratory Cell and Molecular Biology
Kimberly A SmithPaul T Schumacker

Abstract

Pulmonary hypertension (PH) and right ventricular (RV) hypertrophy frequently develop in patients with hypoxic lung disease. Chronic alveolar hypoxia (CH) promotes sustained pulmonary vasoconstriction and pulmonary artery (PA) remodeling by acting on lung cells, resulting in the development of PH. RV hypertrophy develops in response to PH, but coronary arterial hypoxemia in CH may influence that response by activating HIF-1α (hypoxia-inducible factor 1α) and/or HIF-2α in cardiomyocytes. Indeed, other studies show that the attenuation of PH in CH fails to prevent RV remodeling, suggesting that PH-independent factors regulate RV hypertrophy. Therefore, we examined the role of HIFs in RV remodeling in CH-induced PH. We deleted HIF-1α and/or HIF-2α in hearts of adult mice that were then housed under normoxia or CH (10% O2) for 4 weeks. RNA-sequencing analysis of the RV revealed that HIF-1α and HIF-2α regulate the transcription of largely distinct gene sets during CH. RV systolic pressure increased, and RV hypertrophy developed in CH. The deletion of HIF-1α in smooth muscle attenuated the CH-induced increases in RV systolic pressure but did not decrease hypertrophy. The deletion of HIF-1α in cardiomyocytes amplified RV remodeling; t...Continue Reading

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Citations

Aug 14, 2020·American Journal of Respiratory Cell and Molecular Biology·Eva Nozik-Grayck, Larissa A Shimoda
Apr 21, 2021·Journal of Molecular and Cellular Cardiology·Siqin ZhaorigetuMatthew T Harting
Jun 3, 2021·Annals of the American Thoracic Society·Jonathan M Krasinkiewicz, Tim Lahm
Sep 7, 2021·Frontiers in Physiology·Juliane HannemannEdzard Schwedhelm

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Methods Mentioned

BETA
antisense oligonucleotides
Fluorescence
gene knockout

Software Mentioned

Prism
VisualSonics
Transnetyx
Image J
GraphPad

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