Gas biology: small molecular medicine

In this special issue of the Journal of Molecular Medicine, we present five review articles concerning small molecules that play big roles in physiology and medicine: the gases oxygen (O2), nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). Of these, the essential requirement for O2 is well known to physicians, scientists, and laymen alike. However, it is only within the last two decades that we have begun to understand the molecular mechanisms by which every cell in our body senses the local O2 concentration and responds to reduced O2 availability (i.e., hypoxia) with changes in gene expression that are mediated by the hypoxia-inducible factors HIF-1 and HIF-2 [1]. Recent evidence suggest that NO, CO, and H2S function as signaling molecules that also play critical roles in regulating O2 homeostasis. Philip Marsden and colleagues (University of Toronto) describe the fascinating crosstalk between O2 sensing and NO signaling that occurs to regulate red blood cell levels and blood vessel tone, which together play critical roles in O2 delivery [2]. In particular, they discuss exciting data from their lab demonstrating that the physiological responses to anemic hypoxia (reduced O2 carrying capacity) and hypoxic hypoxia (reduced O2) are mechanistically distinct. This difference is dramatically illustrated by their finding that subjecting mice that lack neuronal NO synthase (also known as nNOS or NOS1) to anemic hypoxia resulted in an increased mortality rate, compared to wild-type mice, whereas these NOS1-deficient mice were protected against mortality during hypoxic hypoxia [3]. Their delineation of the molecular and cellular basis for these effects is truly elegant physiology. The crosstalk between O2 sensing and NO signaling is extensive and includes increased expression of inducible NOS (also known as iNOS or NOS2) under hypoxic conditions that is mediated by HIF-1 [4, 5] and the regulation of HIF-1 activity by S-nitrosylation of a cysteine residue in the HIF-1α subunit [6]. Puneet Anand and Jonathan Stamler (Case Western Reserve University) provide a global view of protein Snitrosylation and its effects on protein function [7]. They describe several different molecular mechanisms by which proteins are nitrosylated and counteracting mechanisms by which they are denitrosylated, which is analogous to the phosphorylation and dephosphorylation of proteins by kinases and phosphatases. The balance between nitrosylation and denitrosylation is dependent on the redox state of the cell, thus establishing inherent crosstalk between NO and reactive oxygen species. The authors discuss several examples of diseases associated with dysregulated S-nitrosylation, which may therefore represent a novel therapeutic target. Makoto Suetmatsu and colleagues (Keio University) discuss the biological role of CO, which is generated by heme oxygenases (HO1 and HO2) using heme and O2 as G. L. Semenza (*) Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: gsemenza@jhmi.edu