Gene Transfer of cGMP-Dependent Protein Kinase I Enhances the Antihypertrophic Effects of Nitric Oxide in Cardiomyocytes

Wollert, Kai C.; Fiedler, Beate; Gambaryan, Stepan; Smolenski, Albert; Heineke, Jörg; Butt, Elke; Trautwein, Christian; Lohmann, Suzanne M.; Drexler, Helmut

doi:10.1161/hy1201.097292

Cited by 129 publications

(117 citation statements)

References 41 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…In these cells, lack of NO results in proliferation and hypertrophy (18)(19)(20), suggesting an inhibitory effect of NO on smooth muscle cell growth beneath the well established role of NO in smooth muscle relaxation. Similar effects of NO have been observed in cardiomyocytes, in which signaling by cGMP-dependent kinase I acts as a negative regulator of cardiac myocyte hypertrophy (21), and in Xenopus brain, in which NO is an essential negative regulator of cell proliferation (22).…”

supporting

confidence: 59%

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Saur

Vanderwinden

Seidler

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

Infantile hypertrophic pyloric stenosis (IHPS), characterized by enlarged pyloric musculature and gastric-outlet obstruction, is associated with altered expression of neuronal nitric oxide synthase (nNOS). Here we have studied molecular mechanisms by which nNOS gene expression is altered in pyloric tissues of 16 infants with IHPS and 9 controls. A significant decreased expression of total nNOS mRNA was found by quantitative RT-PCR in IHPS after normalization against GAPDH, which predominantly affected exon 1c with a reduction of 88% compared with controls (P < 0.001). After normalization against the neuronal-specific gene PGP9.5, expression of exon 1c was still decreased (P < 0.001), whereas expression of exon 1f was increased significantly (P ‫؍‬ I nfantile hypertrophic pyloric stenosis (IHPS), with an incidence of 1-5 per 1,000 live births in whites and a marked preponderance of males to females (4:1), is the most frequent disorder requiring surgery in the first year of life (1). A genetic contribution toward the etiology of IHPS is well established with familiar aggregation, a concordance rate of 25-40% in monogenetic twins, a recurrence risk of 10% for males and 2% for females born after an affected child, and a ratio of risk of 18 for first-degree relatives compared with the general population (2).IHPS is characterized by hypertrophy and hyperplasia of the circular muscle layer of the pylorus, leading to persistent vomiting 2-12 weeks after birth (3, 4). Defective pyloric relaxation and increased pyloric smooth muscle mass have been suggested to be responsible for gastric-outlet obstruction. In most cases, surgical pyloromyotomy is the treatment of choice, but conservative management has sometimes been used successfully (5, 6). Within a few months, hypertrophy resolves and no permanent functional or morphological abnormalities have been detected after healing (5,7,8).Recent evidence suggested a reduced expression of neuronal nitric oxide synthase (nNOS) in IHPS, because the pyloric circular muscle layer shows decreased staining of nNOS-positive neurons (9) and decreased expression of nNOS mRNA normalized against GAPDH (10). Additionally, genetic-linkage analysis suggests the nNOS gene as a susceptibility locus for hereditary IHPS (11). In addition to decreased nNOS expression, other abnormalities have been described, such as a reduced amount of interstitial cells of Cajal (12) NO, generated by nNOS, is a major inhibitory transmitter in the gut. It is involved in the intrinsic and extrinsic inhibitory innervation of the pyloric muscle (14), and genetic deletion of nNOS␣ in mice causes a phenotype closely resembling IHPS with delayed gastric emptying, enlargement of the stomach, and hypertrophy of the muscle layer of the antrum (15, 16). Furthermore, deletion of cGMP-dependent kinase I, the downstream target of the NO͞cGMP signaling pathway, leads to a similar phenotype with pyloric stenosis, delayed gastric emptying, and thickened pyloric muscle (17). Additional evidence for an important role of the NO͞cGMP...

show abstract

supporting

confidence: 59%

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Saur

Vanderwinden

Seidler

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

show abstract

“…The effects of PDE1 inhibition on cAMP content in intracellular compartments of cardiac myocytes are likely to differ from those of PDE3 inhibition, perhaps with more favorable sequelae. In animal models, inhibition of cGMP hydrolysis through PDE5 inhibition has been shown to prevent and reverse hypertrophic responses to pressure overload and ␤-adrenergic receptor stimulation and to reduce infarct area size and myocyte apoptosis in injured myocardium (51)(52)(53)(54)(55)(56)(57)(58)(59). PDE1 inhibition might elicit similar benefits.…”

Section: Isoformmentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes

Vandeput

Wolda²,

Krall

et al. 2007

Journal of Biological Chemistry

101

View full text Add to dashboard Cite

Isoforms in the PDE1 family of cyclic nucleotide phosphodiesterases were recently found to comprise a significant portion of the cGMP-inhibited cAMP hydrolytic activity in human hearts. We examined the expression of PDE1 isoforms in human myocardium, characterized their catalytic activity, and quantified their contribution to cAMP hydrolytic and cGMP hydrolytic activity in subcellular fractions of this tissue. Western blotting with isoform-selective anti-PDE1 monoclonal antibodies showed PDE1C1 to be the principal isoform expressed in human myocardium. Immunohistochemical analysis showed that PDE1C1 is distributed along the Z-lines and M-lines of cardiac myocytes in a striated pattern that differs from that of the other major dual-specificity cyclic nucleotide phosphodiesterase in human myocardium, PDE3A. Most of the PDE1C1 activity was recovered in soluble fractions of human myocardium. It binds both cAMP and cGMP with K m values of ϳ1 M and hydrolyzes both substrates with similar catalytic rates. PDE1C1 activity in subcellular fractions was quantified using a new PDE1-selective inhibitor, IC295. At substrate concentrations of 0.1 M, PDE1C1 constitutes the great majority of cAMP hydrolytic and cGMP hydrolytic activity in soluble fractions and the majority of cGMP hydrolytic activity in microsomal fractions, whereas PDE3 constitutes the majority of cAMP hydrolytic activity in microsomal fractions. These results indicate that PDE1C1 is expressed at high levels in human cardiac myocytes with an intracellular distribution distinct from that of PDE3A and that it may have a role in the integration of cGMP-, cAMP-and Ca 2؉ -mediated signaling in these cells. PDE13 cyclic nucleotide phosphodiesterases are dual-specificity enzymes that bind and hydrolyze cAMP and cGMP in a mutually competitive manner (for review, see Ref. 1). Their activity is increased by their binding to Ca 2ϩ and calmodulin, a feature unique to the PDE1 family of cyclic nucleotide phosphodiesterases. Three PDE1 genes, PDE1A, PDE1B, and PDE1C, have been identified, and several protein isoforms are generated from these genes by alternative splicing. PDE1A and PDE1B isoforms have significantly higher affinities for cGMP than for cAMP, whereas PDE1C isoforms have similar affinities for both substrates (2-4). The modulation of the catalytic activity of PDE1 isoforms by Ca 2ϩ -dependent stimulation and their susceptibility to mutually competitive inhibition by cAMP and cGMP suggest that these enzymes may be points of interaction among several signaling pathways.Cyclic nucleotide phosphodiesterases are particularly important in cardiac muscle. In humans, alterations in cAMP metabolism and cAMP-mediated signaling leading to decreases in intracellular cAMP content and in the phosphorylation of some substrates of cAMP-dependent protein kinase are prominent features of the pathophysiology of heart failure, and inhibition of PDE3 cAMP hydrolytic activity has a major role in its treatment (5). Changes in cGMP-mediated signaling in cardiac disease have not been ch...

show abstract

“…Previous studies in cultured cardiac fibroblasts, however, have shown that NO reduces extracellular matrix production. 34 With respect to cardiomyocyte hypertrophy, we have previously shown that NO, by signaling via cGMP-dependent protein kinase type I, inhibits cardiomyocyte hypertrophy and targets the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, 47,48 which may at least in part explain eNOS-dependent inhibition of cardiomyocyte hypertrophy after MI after statin treatment. Though diminished, there was still some effect of statin treatment on cardiomyocyte hypertrophy in eNOS Ϫ/Ϫ mice, suggesting that eNOS-independent mechanisms are also involved in this effect of statin treatment after MI.…”

Section: Landmesser Et Al Statin Therapy and Enos After MImentioning

confidence: 99%

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

et al. 2004

Self Cite

View full text Add to dashboard Cite

Background-Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. Methods and Results-Wild-type (WT) and eNO synthase (eNOS)Ϫ/Ϫ mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS

show abstract

Gene Transfer of cGMP-Dependent Protein Kinase I Enhances the Antihypertrophic Effects of Nitric Oxide in Cardiomyocytes

Cited by 129 publications

References 41 publications

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

Contact Info

Product

Resources

About