Each year cardiovascular disease causes over 4.3 million deaths in Europe and is the cause of nearly one in three deaths in the US. Nitric oxide (NO) is a toxic atmospheric gas which exists in tissues as a biological product of mammalian cells. It has been used to manage cardiovascular disease for over a century and to this day remains an important treatment option in cardiovascular medicine. NO is produced by many cells in the body including vascular endothelial cells. Because of its importance in vascular function, abnormal production of NO, which occurs in different disease states, can adversely affect blood flow and other vascular functions. NO binds to the haem moiety of the enzyme soluble guanylyl cyclase (sGC) which is found in vascular smooth muscle cells and most other cells of the body. NO diffuses from vascular endothelial cells into the vascular smooth muscle cells adjacent to the endothelium where it binds to and activates sGC. sGC is a heterodimer composed of two different subunits: α and β. The structure of sGC consists of a haem-containing regulatory domain, formed by N-terminal portions of both subunits, and a catalytic domain formed by the C-terminal half of both subunits. The N-terminal regions of α and β subunits are often referred to as the regulatory domain of the enzyme. Several isoforms of these subunits have been described: α1 and α2 and β1, β2 and β3. The heterodimer α1β1 is practically present in all tissues studied. In response to NO binding, sGC catalyses the conversion of guanosine-5′-triphosphate (GTP) to cGMP. cGMP is an intracellular messenger and acts on several cGMP-regulated receptor proteins, such as cGMP-stimulated protein kinases, cGMP-regulated phosphodiesterases (PDEs), and cGMP-gated ion channels which subsequently leads to vasorelaxation. Expression levels of sGC have been found altered in several models of cardiovascular disease however the mechanisms behind these alterations remain largely unknown. Several extracellular regulators such as inflammatory ...