HIF in the heart: development, metabolism, ischemia, and atherosclerosis
Andrew Kekūpaʻa Knutson, … , William A. Boisvert, Ralph V. Shohet
Andrew Kekūpaʻa Knutson, … , William A. Boisvert, Ralph V. Shohet
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e137557. https://doi.org/10.1172/JCI137557.
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HIF in the heart: development, metabolism, ischemia, and atherosclerosis

Abstract

The heart forms early in development and delivers oxygenated blood to the rest of the embryo. After birth, the heart requires kilograms of ATP each day to support contractility for the circulation. Cardiac metabolism is omnivorous, utilizing multiple substrates and metabolic pathways to produce this energy. Cardiac development, metabolic tuning, and the response to ischemia are all regulated in part by the hypoxia-inducible factors (HIFs), central components of essential signaling pathways that respond to hypoxia. Here we review the actions of HIF1, HIF2, and HIF3 in the heart, from their roles in development and metabolism to their activity in regeneration and preconditioning strategies. We also discuss recent work on the role of HIFs in atherosclerosis, the precipitating cause of myocardial ischemia and the leading cause of death in the developed world.

Authors

Andrew Kekūpaʻa Knutson, Allison L. Williams, William A. Boisvert, Ralph V. Shohet

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Figure 1

HIF1 expression and function in the developing mouse heart.

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HIF1 expression and function in the developing mouse heart. (A) Mouse he...
(A) Mouse heart development occurs over a period of 7 days, beginning with formation of the cardiac crescent, followed by looping, chamber formation and trabeculation, and finally septation. HIF1α stabilization has been detected at E9.5 in the nascent chambers and outflow track and then becomes restricted to the compact myocardium at E12.5. By E14.5, HIF1α is restricted to the interventricular septum (IVS). (B) Possible targets and functions of HIF1 during heart embryogenesis. HIF1 is thought to promote cardiomyocyte proliferation, glycolysis, and cardiomyocyte specification in embryonic cardiomyocytes. A switch from glycolysis to oxidative phosphorylation is dependent on HIF1α compartmentalization in different regions of the heart over time. LV, left ventricle; RV, right ventricle.