Novel approaches to targeting PDE3 in cardiovascular disease

Inhibitors of PDE3, a family of dual-specificity cyclic nucleotide phosphodiesterases, are used clinically to increase cardiac contractility by raising intracellular cAMP content in cardiac myocytes and to reduce vascular resistance by increasing intracellular cGMP content in vascular smooth muscle myocytes. When used in the treatment of patients with heart failure, PDE3 inhibitors are effective in the acute setting but increase sudden cardiac death with long-term administration, possibly reflecting pro-apoptotic and pro-hypertrophic consequences of increased cAMP-mediated signaling in cardiac myocytes. cAMP-mediated signaling in cardiac myocytes is highly compartmentalized, and different phosphodiesterases, by controlling cAMP content in functionally discrete intracellular microcompartments, regulate different cAMP-mediated pathways. Four variants/isoforms of PDE3 (PDE3A1, PDE3A2, PDE3A3, and PDE3B) are expressed in cardiac myocytes, and new experimental results have demonstrated that these isoforms, which are differentially localized intracellularly through unique protein–protein interactions, control different physiologic responses. While the catalytic regions of these isoforms may be too similar to allow the catalytic activity of each isoform to be selectively inhibited, targeting their unique protein–protein interactions may allow desired responses to be elicited without the adverse consequences that limit the usefulness of existing PDE3 inhibitors.