The role of hypoxia-inducible factors in cardiovascular diseases

https://doi.org/10.1016/j.pharmthera.2022.108186Get rights and content

Abstract

Cardiovascular diseases are the leading cause of death worldwide. During the development of cardiovascular diseases, hypoxia plays a crucial role. Hypoxia-inducible factors (HIFs) are the key transcription factors for adaptive hypoxic responses, which orchestrate the transcription of numerous genes involved in angiogenesis, erythropoiesis, glycolytic metabolism, inflammation, and so on. Recent studies have dissected the precise role of cell-specific HIFs in the pathogenesis of hypertension, atherosclerosis, aortic aneurysms, pulmonary arterial hypertension, and heart failure using tissue-specific HIF-knockout or -overexpressing animal models. More importantly, several compounds developed as HIF inhibitors or activators have been in clinical trials for the treatment of renal cancer or anemia; however, little is known on the therapeutic potential of these inhibitors for cardiovascular diseases. The purpose of this review is to summarize the recent advances on HIFs in the pathogenesis and pathophysiology of cardiovascular diseases and to provide evidence of potential clinical therapeutic targets.

Introduction

Oxygen is an important prerequisite for aerobic respiration, which is essential for cardiovascular systems to maintain cellular homeostasis (Waypa, Smith, & Schumacker, 2016). However, when oxygen supply does not meet cellular energy demand, the body will suffer from hypoxia, and the cells are forced to undergo anaerobic respiration (Sendoel & Hengartner, 2014). Hypoxia leads to cellular dysfunction and even cell death, which is a major cause of cardiovascular diseases (CVDs) including atherosclerosis, pulmonary arterial hypertension (PAH), vascular remodeling, and heart failure (Abe, Semba, & Takeda, 2017; Beaudin, Waltz, Hanly, & Poulin, 2017; Liu et al., 2020). In a hypoxic environment, hypoxia-inducible factor (HIF) is significantly induced and enhanced in cells, which mediates most of the cellular responses to hypoxia at the transcriptional level (Abe et al., 2017; Sousa Fialho, Abd Jamil, Stannard, & Heather, 2019). The activity of HIF-α is regulated at the post-translational level. At normoxic conditions, HIF-α protein is hydroxylated and then degraded by the ubiquitin-proteasome system (Maxwell et al., 1999). In contrast, the HIF-α protein is stabilized in hypoxic cells and translocated into the nucleus to form a heterodimer with the β-subunit (Ham 3rd & Raju, 2017), which then binds to the hypoxia-responsive elements (HRE) and activates the transcription of hypoxia-inducible genes (Hu, Wang, Chodosh, Keith, & Simon, 2003; Schodel et al., 2011).

HIF regulates diverse hypoxia-inducible genes, which are related to angiogenesis, erythropoiesis, and cellular metabolism and inflammation (Melillo et al., 1995; Semenza & Wang, 1992; Tuder, Flook, & Voelkel, 1995; Wheaton & Chandel, 2011). In hypoxic conditions, HIF can initiate adaptive processes to low oxygen availability and mediate protective responses by regulating its downstream targets and relevant signaling pathways in cardiovascular systems (Lee, Ko, Ju, & Eltzschig, 2019; Liu et al., 2020). Therefore, HIF has the potential to become a therapeutic target for the prevention and treatment of CVDs. The objective of this review is to give a systematic summary of HIF functions in CVDs. In addition, the potential clinical therapies involving the modulation of HIF pathways will be discussed.

Section snippets

Hypoxia-inducible factor family

HIFs are a series of members which belong to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor superfamily (Fig. 1). HIF-1 is a heterodimeric transcription factor consisting of an oxygen-sensitive subunit HIF-1α (120kD) and a constitutive subunit HIF-1β (91-94kD) (Semenza & Wang, 1992). HIF-1α is an 826-amino acid protein, whereas HIF-1β protein has 789 amino acids. HIF-1β was first found as a dimerization partner for the aryl-hydrocarbon receptor in the presence of aryl

Hypoxia-inducible factors and cardiovascular development

Many studies have reported that during embryonic cardiovascular development, there exist hypoxia regions, in which the expression of hypoxia-related markers and HIFs is activated in spatial- and time-restricted patterns (Fig. 3). For example, pimonidazole, one of the hypoxia-related markers, was discovered in different regions of the embryo at various time points (Varia et al., 1998). In vitro cultured chick embryos at the early stage showed positive pimonidazole at Hamburger and Hamilton

Hypoxia-inducible factors in various cardiovascular cells

In response to various stimuli, distinct cell types of the vascular wall show different regulation of HIFs and their target genes. For example, HIF-1 can activate angiogenic-related genes such as VEGF in ECs, induce contractile-related myosin light chain phosphorylation in vascular smooth muscle cells (VSMCs), and regulate phenotypic marker expression in adventitial cell differentiation. The following subsections focus on the HIFs expression and activity and their up- and down-stream mediators

Effects of hypoxia-inducible factors on cardiovascular diseases

HIFs-mediated signaling pathways are involved in many kinds of cardiovascular diseases as shown in Table 2 and we will discuss them in detail as below.

Author contributions

BY and AQ conceived this work, BY, XW, YS, GX, SJ and AQ wrote and revised the manuscript. LS, XC and XH draw the figures and tables. All authors contributed to the article and approved the submitted version.

Funding sources

This work was supported by National Key Research and Development Program of China (2021YFA0805100), National Natural Science Foundation of China (81870186; 82070474), the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD201904090; CIT&TCD20190332), and The Key Science and Technology Project of Beijing Municipal Institutions (KZ201910025027; KZ202010025032).

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

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