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

Maurice, Donald H.; Palmer, Daniel; Tilley, Douglas G.; Dunkerley, Heather A.; Netherton, Stuart J.; Raymond, Daniel R.; Elbatarny, Hisham S.; Jimmo, Sandra L.

doi:10.1124/mol.64.3.533

Cited by 293 publications

(272 citation statements)

References 104 publications

(259 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Zhou

et al. 2008

Cell Res

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cAMP and protein kinase A (PKA) are widely known as signaling molecules that are important for the induction of adipogenesis. Here we show that a strong increase in the amount of cAMP inhibits the adipogenesis of 3T3-L1 fibroblast cells. Stimulation of PKA activity suppresses adipogenesis and, in contrast, inhibition of PKA activity markedly accelerates the adipogenic process. As adipogenesis progresses, there is a significant increase in the expression level of PKA regulatory subunits and a corresponding decrease in PKA activity. Moreover, treatment of 3T3-L1 cells with epidermal growth factor (EGF) stimulates PKA activity and blocks adipogenesis. Inhibition of PKA activity abolishes this suppressive effect of EGF on adipogenesis. Moreover, activation of PKA induces serine/threonine phosphorylation, reduces tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and the association between PKA and IRS-1. Taken together, our study demonstrates that PKA has a pivotal role in the suppression of adipogenesis. cAMP at high concentrations can suppress adipogenesis through PKA activation. These findings could be important and useful for understanding the mechanisms of adipogenesis and the relevant physiological events.

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Section: Discussionmentioning

confidence: 99%

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

Wang

Zhou

et al. 2008

Cell Res

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis

et al. 2005

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Background-Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of cardiomyocyte apoptosis remains unclear. Although chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure, the contribution of PDE3 expression/activity in heart failure is not well known. Methods and Results-In this study we report that PDE3A expression and activity were significantly reduced in human failing hearts as well as mouse hearts with chronic pressure overload. In primary cultured cardiomyocytes, chronic inhibition of PDE3 but not PDE4 activity by pharmacological agents or adenovirus-delivered antisense PDE3A promoted cardiomyocyte apoptosis. Both angiotensin II (Ang II) and the ␤-adrenergic receptor agonist isoproterenol selectively induced a sustained downregulation of PDE3A expression and induced cardiomyocyte apoptosis. Restoring PDE3A via adenovirus-delivered expression of wild-type PDE3A1 completely blocked Ang II-and isoproterenolinduced cardiomyocyte apoptosis, suggesting the critical role of PDE3A reduction in cardiomyocyte apoptosis. Moreover, we defined a crucial role for inducible cAMP early repressor expression in PDE3A reduction-mediated cardiomyocyte apoptosis. Conclusions-Our results suggest that PDE3A reduction and consequent inducible cAMP early repressor induction are critical events in Ang II-and isoproterenol-induced cardiomyocyte apoptosis and may contribute to the development of heart failure. Drugs that maintain PDE3A function may represent an attractive therapeutic approach to treat heart failure.

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“…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).…”

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PDE3A mutations cause autosomal dominant hypertension with brachydactyly

et al. 2015

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All Mendelian hypertension syndromes described to date involve increased sodium reabsorption in the distal nephron. 5 The sole exception is autosomal-dominant hypertension with BDE (HTNB, OMIM #112410), first reported in a Turkish kindred. 2,6 HTNB was linked to chromosome 12p in six unrelated families. 2,7,8 The locus accounts for a ~50 mm Hg mean blood pressure difference at age 50 years. 2 The penetrance is 100% (Fig. 1a). Previously, we reported a rearrangement on chromosome 12p common to all families. 8,9 A linkage study in Chinese hypertensive families without BDE coincided with the HTNB locus, supporting relevance to essential hypertension. 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 Supplementary Fig. 1).We detected none of the previously described chromosomal breakpoints on chromosome 12p12.2-12.1, perhaps due to high repetitive content in the breakpoint regions Fig. 2a-c). 4 A haplotype analysis identified a novel recombination that reduced the linkage interval and eliminated an inversion common to all affected individuals in the six families (Fig. 2c). 9 In contrast, the affected mother's haplotype showed co-segregation with the more severe brachydactyly phenotype.PDEs are involved during early stages of osteogenesis. 12 PDE4D mutations have been associated with severe brachydactyly in acrodysostosis. 13,14 In mice, Pde3a was expressed in the developing limbs, consistent with a role during chondrogenesis (Fig. 2d, Supplementary Fig. 3a, b). Chondrogenic downregulation of PTHLH encoding PTHrP was associated with BDE. 15 We also observed PTHLH downregulation in chondrogenically induced fibroblasts from affected persons (Fig. 2e, Supplementary Fig. 3c).We addressed the functional consequences of the identified PDE3A mutations in HeLa cells expressing the six mutations. Forskolin or L-arginine stimulated the adenylate or guanylate cyclases to enhance cellular cAMP or cGMP levels, respectively. 16,17 We detected significantly reduced cAMP levels, consistent with gain-of-function mutations with no change in cGMP levels for the PDE3A mutations ( Supplementary Fig. 4a, b). Three PDE3A isoforms, PDE3A1 (microsomal), PDE3A2 and PDE3A3 (microsomal and cytosolic), have been identified in human myocardium. 18,19 PDE3A3 does not contain the sequence harboring the detected mutations. The predominant isoform in VSMC is PDE3A2. 18,20 To directly elucidate the mutations' effects, we compared the Michaelis-Menten kinetics of cAMPhydrolytic activity for recombinant T445N FLAG-tagged PDE3A1 and PDE3A1-WT and the tagged A2 isoforms purified from transfected cells (Fig. 3a, b, Supplementary Fig. 4d-k). The T445N mutation increased the affinity of both enzyme's isoforms for cAM...

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

Cited by 293 publications

References 104 publications

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

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

Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

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