Hypoxia Inducible Factors as Central Players in the Pathogenesis and Pathophysiology of Cardiovascular Diseases

Abstract

Cardiovascular (CV) diseases are the major cause of death in industrialized countries. The main function of the CV system is to deliver nutrients and oxygen to all tissues. During most CV pathologies, oxygen and nutrient delivery is decreased or completely halted. Several mechanisms, including increased oxygen transport and delivery, as well as increased blood flow are triggered to compensate for the hypoxic state. If the compensatory mechanisms fail to sufficiently correct the hypoxia, irreversible damage can occur. Thus, hypoxia plays a central role in the pathogenesis and pathophysiology of CV diseases. Hypoxia inducible factors (HIFs) orchestrate the gene transcription for hundreds of proteins involved in erythropoiesis, glucose transport, angiogenesis, glycolytic metabolism, reactive oxygen species (ROS) handling, cell proliferation and survival, among others. The overall regulation of the expression of HIF-dependent genes depends on the severity, duration, and location of hypoxia. In the present review, common CV diseases were selected to illustrate that HIFs, and proteins derived directly or indirectly from their stabilization and activation, are related to the development and perpetuation of hypoxia in these pathologies. We further classify CV diseases into acute and chronic hypoxic states to better understand the temporal relevance of HIFs in the pathogenesis, disease progression and clinical outcomes of these diseases. We conclude that HIFs and their derived factors are fundamental in the genesis and progression of CV diseases. Understanding these mechanisms will lead to more effective treatment strategies leading to reduced morbidity and mortality.

Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction—Molecular Mechanisms and Clinical Significance

“…Hydroxylation enables binding of HIFs to the ubiquitin proteasome system and subsequent degradation; inhibition of this degradation pathway in hypoxia activates HIF-mediated gene transcription (75,76).…”

“…The best known transcriptional regulators of the physiological responses are the hypoxia-inducible factors (HIF). HIF-1α is activated acutely upon oxygen deficiency, whilst HIF-2α mediates the sustained responses to prolonged hypoxia ( 75 ). By this mechanism, hypoxia elicits a systemic hemodynamic response via activation of the carotid chemokine receptors and systemic humoral mechanisms.…”

“…During normoxia, the HIF-1α protein is hydroxylated by prolyl hydroxylases that are absolutely dependent on the presence of oxygen. Hydroxylation enables binding of HIFs to the ubiquitin proteasome system and subsequent degradation; inhibition of this degradation pathway in hypoxia activates HIF-mediated gene transcription ( 75 , 76 ).…”

Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls

“…A recent publication by Pedrosa and Lemes showed a decreased expression of hypoxia inducible factors (HIFs) in the setting of hydroxyurea 69 . While the relationship between HIFs and cardiovascular disease is well‐established, it is unclear whether induction of HIFs is beneficial or detrimental in the setting of cerebral hemodynamic compromise 70 . Ultimately, the relationship between hemoglobin F and metrics of cerebral hemodynamic stress warrants further investigation as it not only pertains to patients with SCA in the setting of current treatment with hydroxyurea, but also with novel therapeutic options that induce hemoglobin F production or modify hemoglobin's oxygen affinity 71,72 .…”

“…69 While the relationship between HIFs and cardiovascular disease is well-established, it is unclear whether induction of HIFs is beneficial or detrimental in the setting of cerebral hemodynamic compromise. 70 Ultimately, the relationship between hemoglobin F and metrics of cerebral hemodynamic stress warrants further investigation as it not only pertains to patients with SCA in the setting of current treatment with hydroxyurea, but also with novel therapeutic options that induce hemoglobin F production or modify hemoglobin's oxygen affinity. 71,72 Furthermore, this line of investigation would potentially be relevant to neonatal patient populations and patients with ineffective erythropoiesis (e.g., thalassemia, congenital dyserythropoietic anemia) that commonly have increased hemoglobin F.…”