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.