Associated labs

Chemistry and pharmacology of the chemical interaction of nitric oxide with sulfide in red blood cells

By studying the chemical interaction of nitric oxide and sulfide under physiological conditions we discovered that chemical reactions occur between nitric oxide and sulfide leading to the formation of polysulfide and S-N hybrid species including SSNO- ( a NO and persulfide donor) and sulfiNO (nitroxyl and NO donor). These species induce vasodilation and modulate cardiac contractility both ex vivo and in vivo. Interestingly we found that red blood cells may play a central role in systemic sulfide metabolism: red blood cells produce sulfide and polysulfide and release these products in the supernatant in a reaction catalyzed by methemoglobin. Thereby, sulfide reduces methemoglobin back to deoxy/oxyhemoglobin, indicating the sulfide metabolic pathway in red blood cells may contribute to keeping hemoglobin in its reduced oxygen-binding form. 

The role of a nitric oxide synthase in red blood cells for circulating nitrite homeostasis and systemic hemodynamics

According to experiments carried out by using bone marrow transplantation chimera mice, there is strong evidence that eNOS in the blood may contribute to systemic circulating nitrite levels, blood pressure regulation, and cardioprotection.

L-Arginine / nitric oxide signaling in the regulation of red cell function and dysfunction

We found that red blood cells carry full Arginase1 (Arg1)/eNOS/soluble guanylate cyclase (sGC) signaling pathway and downstream signaling. Surprisingly, we found that eNOS produces NO in red blood cells under normoxic conditions. The pathophysiological role of L-Arginine/NO signaling in red blood cells for red blood cell function and dysfunction is still not clear yet. We found that nitric oxide signaling does not regulate red cell deformability per se, rather protects red blood cells from oxidant damage. Moreover, we studied whether L-Arg/NO signaling in red blood cells may regulate ATP release from red blood cells and found it to be independent of both cGMP and cAMP. We are currently analyzing the effects of red blood cell-specific genetic deletion of Arg1, eNOS, and sGC in vivo in mice obtained by the loxP/Cre technology on L-Arginine metabolism and red cell functional properties, including mechanical properties, the release of NO bioactivity, and vasodilation, cardioprotective activity ex vivo.

Nitric oxide as a central player for cellular and systemic redox physiology

Nitric oxide plays a complex role in redox physiology acting as a signaling molecule, inducing post-translational modifications on cysteines, and participating in the regulation of the redox state. In my laboratory, we found that NO produced by the endothelial nitric oxide synthase is upregulated in a model of systemic oxidative stress induced by lack of the transcription factor Nrf2, and thereby fully preserves endothelial function and protect the heart from ischemic damage after acute myocardial infarction.