Abstract
Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions.
Highlights
Cardiovascular disease is the number one cause of death worldwide and remains a burdensome health problem
En face analysis found that TSP1 inhibited ionophoremediated calcium wave propagation on the endothelium monolayer (Bauer et al, 2010). This is in contrast to TSP1 activity in Jurkat T cells, where both the whole protein and a recombinant C-terminal domain(E123CaG1) that we previously demonstrated interacts selectively with CD47 (Isenberg et al, 2009a), increased cytosolic Ca2+ and inhibited soluble guanylate cyclase (sGC) (Ramanathan et al, 2011)
The TSP1-derived CD47 activating domain E123CaG1 inhibited YC-1- and BAY 41-2272-mediated stimulation of sGC. This inhibition could only be reversed by adding back exogenous Nitric oxide (NO) (Ramanathan et al, 2011). This finding may be of clinical relevance, as NO-independent stimulators and activators of sGC are being developed for use in diseases, including pulmonary hypertension (Mittendorf et al, 2009), in which NO signaling is reduced or absent (Rabinovitch, 2007; Stasch and Evgenov, 2013) and, as we have shown, TSP1-CD47 signaling concurrently upregulated (Bauer et al, 2012)
Summary
Cardiovascular disease is the number one cause of death worldwide and remains a burdensome health problem. Exogenous TSP1, the recombinant type 1 repeat protein domain of TSP1, and a CD36-targeting peptide (based on the proposed CD36 binding site of TSP1) all limited NO-stimulated effects including proliferation and migration of vascular endothelial cells (Isenberg et al, 2005b).
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