The Roles of hypoxia signaling in sterile inflammation and tissue remodeling

Abstract

Hypoxia is a condition in which the tissue is deprived of adequate oxygen supply. It occurs in several cardiovascular disorders, such as cardiac hypertrophy and myocardial ischemia, and accelerates the inflammatory processes. While each cell exerts its own responses to hypoxia, most of them are mainly mediated through the transcription factor, hypoxia inducible factor-1a (HIF-1a) and HIF-2a. Macrophages are key mediators of inflammation, and can be broadly classified as M1 (pro-inflammatory) and M2 (anti-inflammatory) type. We found that HIF-1a and HIF-2a is specifically expressed in M1 and M2 macrophages respectively. The balance between HIF-1a and HIF-2a, termed as HIF-a switching, regulates macrophage activation and its resolution. We further examined the roles of macrophage hypoxia signaling in cardiac remodeling using mice transverse aortic constriction model, and found that M1 macrophages accumulate into the hypoxic area though a HIF-1a dependent manner. As an underlying molecular mechanism, we discovered that HIF-1a mediated glycolytic reprograming is critically required in macrophage migration potential. Importantly, LV hypertrophy and cardiac fibrosis were more prominent while systolic function was impaired in HIF-1a knockout mice. These results demonstrate a novel functional link between hypoxia activated cardiac macrophage and cardiovascular remodeling.