For a long time red blood cells have been considered as transporters of oxygen and nutrients to the tissue, and less as compartments actively contributing to cardiovascular homeostasis. Accumulating evidence from our and other laboratories has demonstrated that red blood cells directly participate to metabolism of nitric oxide, an important messenger produced by the endothelium of the vessels. Recently we have demonstrated that red blood cells carry a functional endothelial NO-synthase (NOS3) (i.e. the same enzyme producing NO in the vessels (Cortese-Krott et. al Blood 2012), and that circulating blood NOS3 contributes to the regulation of systemic blood pressure and nitrite homeostasis (Wood, Cortese-Krott et al ATVB 2013), and play a role in cardioprotection against ischemia/reperfusion injury (Merx, Gorressen et al., Basic Res Cardiol 2014). Our current research projects aim to understand a specific role of NO synthesis in red blood cells as compared to endothelial cells in the regulation of vascular tone, blood pressure and cardioprotection. A number of recently developed in our laboratory conditional tissue specific knock-out and knock-in mouse models enable us to inactivate or re-introduce genes of interest regulating NO synthesis, NO signaling and bioavailability in specific tissue and/or at a specific time point, while in other tissues the gene remains either functionally active with the wild type expression or functionally inactive with global knock-out expression, accordingly. The chemical, biochemical and in vivo cardiovascular characterization of these mice, together with the analysis of the same parameter in clinical cohorts will shed light on the role of red blood cell in pathophysiology of cardiovascular system, and contribute to identify new diagnostic and therapeutic targets.
Nitric oxide and hydrogen sulfide were first considered as toxic gases. The discovery that they can be produced endogenously in mammalian tissues by a battery of highly conserved enzymes has completely changed this prospective. In recent years it was shown that nitric oxide and sulfide exert similar, partially interdependent effects in the cardiovascular system characterized by both limitation or enhancement of their physiological and pharmacological effects, particularly in the control of blood pressure regulation. We recently found that nitric oxide and sulfide react with eachother leading to formation of three classes of bioactive intermediates (SSNO-, polysulfide and SULFI/NO), each of them exerting specific effects in the cardiovascular system (Cortese-Krott, PNAS 2015). Further work of our group is focused on chemical biology and bioactivity of key reaction products formed in the NO/sulfide system and on its significance for cardiac and vascular function.