Nitric oxide signaling in hypoxia

Abstract

Endothelial-derived nitric oxide (NO) is classically viewed as a regulator of vasomotor tone. NO plays an important role in regulating O(2) delivery through paracrine control of vasomotor tone locally and cardiovascular and respiratory responses centrally. Very soon after the cloning and functional characterization of the endothelial nitric oxide synthase (eNOS), studies on the interaction between O(2) and NO made the paradoxical finding that hypoxia led to decreases in eNOS expression and function. Why would decreases in O(2) content in tissues elicit a loss of a potent endothelial-derived vasodilator? We now know that restricting our view of NO as a regulator of vasomotor tone or blood pressure limited deeper levels of mechanistic insight. Exciting new studies indicate that functional interactions between NO and O(2) exhibit profound complexity and are relevant to diseases states, especially those associated with hypoxia in tissues. NOS isoforms catalytically require O(2). Hypoxia regulates steady-state expression of the mRNA and protein abundance of the NOS enzymes. Animals genetically deficient in NOS isoforms have perturbations in their ability to adapt to changes in O(2) supply or demand. Most interestingly, the intracellular pathways for O(2) sensing that evolved to ensure an appropriate balance of O(2) delivery and utilization intersect with NO signaling networks. Recent studies demonstrate that hypoxia-inducible factor (HIF) stabilization and transcriptional activity is achieved through two parallel pathways: (1) a decrease in O(2)-dependent prolyl hydroxylation of HIF and (2) S-nitrosylation of HIF pathway components. Recent findings support a role for S-nitrosothiols as hypoxia-mimetics in certain biological and/or disease settings, such as living at high altitude, exposure to small molecules that can bind NO, or anemia.

Hypoxia causes increased monocyte nitric oxide synthesis which is mediated by changes in dimethylarginine dimethylaminohydrolase 2 expression in animal and human models of normobaric hypoxia

“…By contrast, in the human samples, only a trend towards increased eNOS expression was observed. This is consistent with studies showing that in the absence of a pro inflammatory cytokine, iNOS induction is not observed in human hypoxia 40 . A number of studies have demonstrated previously that eNOS is present in human monocytes.…”

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

“…Indeed, decreased eNOS expression and function has been implicated in the pathology of a number of cardiovascular diseases, including atherosclerosis and hypertension (1,5), and is a key defining feature of the clinical entity termed endothelial dysfunction. Significantly, hypoxia is a major cellular stress that has a profound impact on endothelial cell biology, including critical changes in gene expression (6,7). Thus, understanding the molecular regulation of eNOS gene expression is a high-priority area.…”

Mesangial renal disease, oxygen sensing, and prolyl hydroxylase

“…NO synthase isoforms require oxygen. Ho et al emphasized that HIF stabilization and transcriptional activity is achieved through two parallel pathways: first, a decrease in oxygen-dependent prolyl hydroxylation of HIF and second, the S-nitrosylation of HIF pathway components [8]. NO is one of the few gaseous signaling molecules known and is additionally exceptional as a radical gas.…”