Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

Abstract

Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

Spatial Dynamics of the Developing Human Heart

“…Furthermore, we found a spatial cluster characterized by high expression of cardiomyocyte stress- and hypoxia response-related genes ( ACTA1 , NPPB , ENO1 , LDHA, MIF, FAM162A ) 24,25 positioned around the papillary muscles (PM), reflecting mechanical strain on these structures (Fig. 1f, Suppl.…”

Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics—a narrative review

“…In mammals, the α-subunit is found in three isoforms: HIF-1α, HIF-2α, and HIF-3α [ 12 ]. HIF-1α is typically linked to acute hypoxia and is accountable for activating glycolytic genes, reducing oxygen consumption, and alleviating reactive oxygen species (ROS) production [ 8 ].…”

“…The stability of HIF-2α mRNA levels exceeds that of HIF-1α mRNA [ 16 ]. HIF-2α enhances erythropoietin (EPO) synthesis, manages iron metabolism, regulates fatty acid synthesis and uptake, and significantly influences chronic inflammation, fibrosis, and tumorigenesis [ 8 ]. Although less explored than HIF-1α and HIF-2α, HIF-3α also holds significance in the hypoxia response.…”

“…Hypoxia acts as the link connecting the pathophysiological changes in sepsis to the molecular alterations of hypoxia-inducible factor-1α (HIF-1α). Specifically, HIF-1α levels are intricately regulated by oxygen, undergoing degradation under normoxic conditions and accumulation in hypoxic environments [ 8 ]. HIF-1α is a heterodimeric protein complex that serves as a critical regulator of the cellular response to physiological hypoxia and infection, exerting diverse pathophysiological effects at the cellular, tissue, and organismal levels [ 9 – 11 ].…”

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…For example, although the cardiomyocyte-specific deletion of Hif2 α (but not HIF1 α) increased infarct sizes in a mouse model of ischemia-reperfusion injury (Koeppen, Lee et al 2018), the inhibition of Hif2 α reversed right heart failure and pulmonary arterial hypertension in rodents(Dai, Zhu et al 2018). Pharmacological inhibition of HIF2a, such as PT2567, has been reported to improve pulmonary, vascular remodeling and hemodynamics in several preclinical models of established PH (Hu, Poth et al 2019, Macias, Moore et al 2021) Contrarily, the coronary microvasculature’s unique dilation in hypoxic conditions, as opposed to pulmonary artery constriction, raises questions(Sylvester, Shimoda et al 2012, Marano, Wei et al 2023, Zhao, Xiong et al 2023), and this response is pivotal for enhancing oxygen supply to the myocardium. Consequently, the net effect of HIF2a inhibition on ischemic heart conditions, whether beneficial or detrimental, remains to be elucidated.…”