The Roles of Hypoxia Signaling in the Pathogenesis of Cardiovascular Diseases

The circulatory system distributes blood flow to each tissue and transports oxygen and nutrients. Peripheral circulation is required to maintain the physiological function in each tissue. Disturbance of circulation, therefore, decreases oxygen delivery, leading to tissue hypoxia which takes place in several cardiovascular disorders including atherosclerosis, pulmonary arterial hypertension and heart failure. While tissue hypoxia can be induced because of cardiovascular disorders, hypoxia signaling itself has a potential to modulate tissue remodeling processes or the severity of the cardiovascular disorders. Hypoxia inducible factor-1 alpha (HIF-1 alpha) and HIF-2 alpha belongs to a group of transcription factors which mediate most of the cellular responses to hypoxia at a transcriptional level. We, and others, have reported that HIF-alpha signaling plays a critical role in the initiation or the regulation of inflammation. HIF-alpha signaling contributes to the tissue remodeling processes; thus it has a potential to become a therapeutic target. Elucidation of the molecular link, therefore, between hypoxia signaling and tissue remodeling will greatly help us to understand the pathophysiology of the cardiovascular disorders. The purpose of this review is to give a brief overview of the current understanding about the function HIF-alpha in inflammation processes especially by focusing on its roles in macrophages. In addition, the pathophysiological roles of hypoxia signaling for the development of cardiovascular disease will be discussed.