Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow.
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.
Department of Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
Natasha M
NM
Rogers
Department of Chemistry and Biochemistry, University of Maryland Baltimore County Baltimore, MD, USA.
Franziska
F
Seeger
Department of Chemistry and Biochemistry, University of Maryland Baltimore County Baltimore, MD, USA.
Elsa D
ED
Garcin
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH Bethesda, MD, USA.
David D
DD
Roberts
Department of Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine Pittsburgh, PA, USA ; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
Jeffrey S
JS
Isenberg
CD47; ROS; cardiovascular disease; cyclic guanosine monophosphate; nitric oxide; soluble guanylate cyclase; thrombospondin-1