A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Human endothelial and aortic smooth muscle cells were exposed either to A) normoxia (21% O2) for three weeks, or to B) mild decreased oxygen (15% O2) for three weeks to mimic blood oxygen levels in patients with heart failure, or to C) mild decreased oxygen for two weeks followed by one week of normoxia ("memory" treatment). Levels of HIF signaling genes (HIF-1α, HIF-2α, VEGF, BNIP3, GLUT-1, PAI-1 and iNOS) were measured both at the protein and mRNA levels.It was found that chronic exposure to mild decreased oxygen resulted in significantly increased HIF signaling. There was also a "memory" of HIF-1α and HIF target gene induction when oxygen levels were normalized for one week, and this "memory" could be interrupted by adding a small molecule HIF inhibitor to the last week of normalized oxygen. Finally, levels of ubiquitylated HIF-1α were reduced in response to chronic mild decreased oxygen and were not full restored after oxygen normalization.These data suggest that HIF signaling may be contributing to the pathogenesis of endothelial dysfunction and that normalization of oxygen levels may not be enough to reduce vascular stress.Endothelial dysfunction has been shown to play a causative role in atherosclerosis [1], ischemic heart disease [2], coronary artery disease [3], peripheral neuropathy [4], diabetic cardiomyopathy [5], erectile dysfunction [6] and even ischemia/reperfusion subsequent to myocardial infarction [7]. Endothelial dysfunction is a generalized syndrome characterized by attenuated vasodilation [8], due at least in part to decreased available nitric oxide (NO) [9], a concomitant buildup of reactive species [10] and stimulation of vascular stress pathways [11]. Another characteristic of endothelial dysfunction is an altered angiogenic response [12], which can affect tissue vascularity, immune cell infiltration, blood flow patterns, and wound healing (reviewed in [11]). If the blood vessels cannot supply the tissues with blood, a state of relative decre