Red Blood Cells as a "Central Hub" for Sulfide Bioactivity: Scavenging, Metabolism, Transport, and Cross-Talk with Nitric Oxide

Significance: Sulfide was revealed to be an endogenous signaling molecule regulating a plethora of cellular functions. It is involved in the regulation of fundamental processes, including blood pressure regulation, suspended animation, and metabolic activity of mitochondria, pain, and inflammation. The underlying biochemical pathways and pharmacological targets are still largely unidentified. Recent Advances: Red blood cells (RBCs) are known as oxygen transporters and were proposed to contribute to cardiovascular homeostasis by regulating nitric oxide (NO) metabolism, also via interaction of hemoglobin with nitrite and NO itself. Interestingly, recent evidence indicates that RBCs may also play a central role in systemic sulfide metabolism and homeostasis, and, potentially, in the crosstalk with NO. Heme-containing proteins such as hemoglobin were shown to be targeted by both NO and sulfide. In this article, we aim at revising and discussing the potential impact of RBCs on systemic sulfide metabolism in the cardiovascular system. Critical Issues: Although the synthetic pathways and the reactivity of hemoglobin and other heme proteins with sulfide and NO are known, the in vivo role of RBCs in sulfide metabolism, physiology, pharmacology, and its pathophysiological implications have not been characterized so far. Future Directions: To allow a better understanding of the role of RBCs in systemic sulfide metabolism and its cross-talk with NO, basic and translational science studies should be focused on dissecting the enzymatic and nonenzymatic sulfur metabolic pathways in RBCs in vivo and their impact on the cardiovascular system in animal models and clinical settings.