The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

Abstract

Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

Selected Exogenous (Occupational and Environmental) Risk Factors for Cardiovascular Diseases in Military and Aviation

“…In this condition, HIF-1 exerts cardioprotective effects by alleviating ROS generation and stimulating the removal of unwanted mitochondria through mitophagy. In chronic hypoxic conditions, HIF-1 increases ROS levels, stimulates inflammasome gene expression (including the interleukin 1ß (IL-1ß) gene), and contributes to atherosclerosis development, which in turn confirms the importance of hypoxia in CVD development [27][28][29].…”

Quantitative assessment of retinal vasculature changes in systemic lupus erythematosus using wide-field OCTA and the correlation with disease activity

“…Second, patients with high disease activity are in a state of intense inflammatory response. Hypoxia is a common feature of most inflammation, and conversely, it is also an important factor for inflammation induction or exacerbation ( 29 ). Third, there have been clinical studies investigating the vasculature changes by OCTA.…”

Effect of Diosmin on Selected Parameters of Oxygen Homeostasis

“…HIF signaling plays a crucial role in the response to hypoxia, which is often associated with various cardiovascular diseases. HIF promotes vascularization in hypoxic areas and also participates in modulating the inflammatory state [ 11 , 12 ]. In chronic venous disease, the dysregulation of the HIF pathway leads to abnormal expression of angiogenic factors.…”