Phosphodiesterase-1 in the cardiovascular system

Phosphodiesterases regulate levels of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate. Thanks to regulation by specific phosphodiesterase subtypes and isoforms in differential intracellular nanodomains, these versatile, ubiquitous signaling molecules can exert specific effects. This regulation depends on cell type and the (patho)physiological conditions in which these cells reside. In this review phosphodiesterase 1 is highlighted with respect to its structure, function and exploitation as a drug target for modulation of cardiovascular function. The function of its various isoforms in vascular smooth muscle, cardiac myocytes and fibroblasts are discussed. This comprises vasomotor control, cardiac myocyte contractility, growth control, fibrosis and senescence. The conditions that modulate phosphodiesterase 1 and the clinical relevance of this modulation are summarized. These conditions include proliferative status, cell stress, and aging. Furthermore, important associated signaling mechanisms and the implication of nanodomains are described. Also, the prospective of using PDE1 inhibitors as clinical drugs in cardiovascular disease is addressed.

Automated summary

This review focuses on the role of phosphodiesterases in regulating the levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Specifically, phosphodiesterase 1 is highlighted, discussing its structure, function, and potential as a drug target for cardiovascular modulation. The various isoforms of phosphodiesterase 1 in different cell types and their effects on vasomotor control, cardiac myocyte function, growth control, fibrosis, and aging are explored. The modulation of phosphodiesterase 1 in different physiological conditions and its clinical relevance are summarized, along with the involvement of nanodomains. The potential use of PDE1 inhibitors as clinical drugs for cardiovascular disease is also discussed.