Cyclic Nucleotide Phosphodiesterase Activity, Expression, and Targeting in Cells of the Cardiovascular System

Abstract

Cyclic AMP (cAMP) and cGMP regulate a myriad of cellular functions, such as metabolism, contractility, motility, and transcription in virtually all cell types, including those of the cardiovascular system. Considerable effort over the last 20 years has allowed identification of the cellular components involved in the synthesis of cyclic nucleotides, as well as effectors of cyclic nucleotide-mediated signaling. More recently, a central role for cyclic nucleotide phosphodiesterase (PDE) has also been elaborated in many cell types, including those involved in regulating the activities of the cardiovascular system. In this review, we introduce the PDE families whose members are expressed in cells of the cardiovascular system including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. Because cell behavior is a dynamic process influenced by numerous factors, we will attempt to emphasize how changes in the activity, expression, and targeting of PDE influence cyclic nucleotide-mediated regulation of the behavior of these cells.The cyclic nucleotides cAMP and cGMP regulate a myriad of cellular functions, including metabolism, contractility, motility, and transcription in virtually all cell types, including those of the cardiovascular system (Antoni, 2000;Klein, 2002). Although early work identified cAMP and cGMP as second messengers and led to the discovery of the proteins involved in coordinating the synthesis, degradation, and cellular actions of cyclic nucleotides, early models describing how these systems allowed cyclic nucleotide-mediated regulation of multiple cellular functions underestimated the levels of flexibility and specialization involved. In this context, recent work has identified large numbers of receptor (Marchese et al., 1999;Lucas et al., 2000), adenylyl cyclase (Hanoune and Defer, 2001), guanylyl cyclase (Garbers, 1999;Lucas et al., 2000), heterotrimeric G-protein (Marchese et al., 1999), and cyclic nucleotide phosphodiesterase (PDE) (Beavo and Reifsnyder, 1990;Beavo, 1995;Conti et al., 1995;Manganiello and Degerman, 1999;Conti, 2000;Conti and Jin, 2000;Houslay and Kolch, 2000;Soderling and Beavo, 2000;Francis et al., 2001;Houslay and Adams, 2003) protein families. Although many of the cellular effects of cAMP and cGMP are coordinated through their activation of cyclic nucleotide-dependent protein kinases (Lincoln et al., 1995), several other effectors are now known. Thus, cyclic nucleotidegated ion channels (Yau, 1994), cAMP-activated guanine nucleotide exchange factors (de Rooij et al., 1998;Kawasaki et al., 1998), and cyclic nucleotide PDEs have each been shown to transduce cyclic nucleotide-encoded information (Beavo and Reifsnyder, 1990;Beavo, 1995;Conti et al., 1995;Manganiello and Degerman, 1999;Conti, 2000;Conti and Jin, 2000;Houslay and Kolch, 2000;Soderling and Beavo, 2000;Francis et al., 2001;Houslay and Adams, 2003). More recently, an appreciation of the impact of regulated anchoring/targeting of cyclic nucleotide-regulated proteins to discrete subcell...

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

“…As a non-specific inhibitor of phosphodiesterases, the signaling induced by MIX is closely related to that induced by phosphodiesterases. At present, more than 50 variants of the mammalian phosphodiesterase isoenzyme, which shows differential hydrolytic activities on cAMP and cGMP, have been identified [38]. This suggests another possibility that the cellular responses to MIX could be different owing to the different cell types or to the different expression patterns of phosphodiesterases.…”

Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis

“…Of note, there is no cardiac abnormality in PDE3A Ϫ/Ϫ mice, although PDE3A is the major PDE3 isoform in cardiac muscle and PDE3 inhibitors show great effects on cardiac contractility. 29 It is possible that depletion of PDE3A alone may not be sufficient to induce cardiac injury in vivo, although PDE3A is essential in cardiomyocyte survival. Thus, additional challenge of PDE3A Ϫ/Ϫ mice with "stress" such as chronic pressure overload by TAC might be required to induce cardiac dysfunction.…”

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

“…10 Whole-genome sequencing of Turkish family members revealed a heterozygous missense mutation in PDE3A (Gene ID: 5139), a gene encoding a cGMP/cAMP phosphodiesterase with a prominent role in the heart, VSMC, oocytes and platelets. 11 Resequencing of all 48 affected persons in six unrelated families identified six independently clustered heterozygous missense mutations in exon 4 (Fig. 1a, b, 2a, Supplementary Table 1).…”