PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways

2014 ◽  
Vol 306 (8) ◽  
pp. H1246-H1252 ◽  
Author(s):  
C. Vettel ◽  
S. Lämmle ◽  
S. Ewens ◽  
C. Cervirgen ◽  
J. Emons ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Sodium Nitroprusside ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Nitric Oxide Donor ◽  
Signal Molecules ◽  
Protective Mechanism ◽  
Camp Hydrolysis ◽  
Camp And Cgmp ◽  
Atrial Natriuretic

Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.

Endothelin increases the synthesis and secretion of atrial natriuretic peptide in neonatal rat cardiocytes

1991 ◽  
Vol 261 (2) ◽  
pp. E177-E182 ◽  
Author(s):  
D. G. Gardner ◽  
E. D. Newman ◽  
K. K. Nakamura ◽  
K. P. Nguyen
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Primary Cultures ◽  
Secretory Activity ◽  
Neonatal Rat ◽  
Regulatory Function ◽  
Mrna Accumulation ◽  
Calmodulin Antagonist ◽  
Natriuretic Hormone ◽  
Atrial Natriuretic

Endothelin (ET) effected a dose-dependent increment in atrial natriuretic peptide (ANP) secretion and ANP mRNA accumulation in neonatal rat atrial and ventricular cardiocytes but had no effect on the processing of the ANP prohormone to the mature ANP product. The secretagogue effect was not limited by cell density. Both basal and ET-dependent secretory activity were abrogated by the calmodulin antagonist calmidazolium but were unaffected by meclophenamate or pertussis toxin. The magnitude of the ET-dependent increment in ANP secretion was amplified by culturing the cells in a dynamically pulsating (vs. static) environment, implying an interaction between mechanical and agonist-mediated secretory stimuli in this system. ET also promoted immunoreactive ANP release from primary cultures of fetal rat hypothalamic cultures, suggesting that this regulatory function may be generally employed in ANP gene-expressing cells. These findings demonstrate that ET has parallel effects on ANP synthesis and secretion and support a role for this peptide in the regulation of local and circulating levels of the natriuretic hormone.

scholarly journals Divergent regulation of the human atrial natriuretic peptide gene by c-jun and c-fos.

1992 ◽  
Vol 12 (1) ◽  
pp. 292-301 ◽  
Author(s):  
B Kovacic-Milivojević ◽  
D G Gardner
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Transcriptional Activation ◽  
Gene Promoter ◽  
Regulatory Elements ◽  
Neonatal Rat ◽  
Regulatory Sequence ◽  
Mobility Shift ◽  
Human Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

Employing transient transfection analysis in neonatal rat cardiocytes, we have demonstrated that overexpression of c-jun results in a dose-dependent induction of the human atrial natriuretic peptide (hANP) gene promoter. Studies using a series of mutations in the hANP gene promoter identified a TRE-like, cis-acting regulatory sequence which conferred c-jun sensitivity. This same region was shown to interact with the c-jun/c-fos complex in an in vitro gel mobility shift assay. Selective mutation of this site suppressed basal activity of the hANP promoter and significantly reduced c-jun-dependent activation. Overexpression of c-fos had a biphasic effect on hANP gene promoter activity. At low levels, in concert with c-jun, it activated, while at higher levels it suppressed, transcription from the hANP gene promoter. This inhibition was both cell and promoter specific. hANP gene promoter sequences which mediate c-fos-dependent inhibition appear to be separable from those responsible for the induction. In addition, the protein domains on c-fos responsible for transcriptional activation and repression can be segregated topographically, with the inhibitory activity being localized to the carboxy-terminal domain. Thus, c-fos can activate or repress hANP gene expression through two separate functional domains that act on distinct regulatory elements in the hANP gene promoter. These data imply that the ANP gene may be a physiological target for c-fos- and c-jun-dependent activity in the heart and suggest a potential mechanism linking environmental stimuli to its expression.

Atrial natriuretic peptide gene expression and its secretion by pneumocytes derived from neonatal rat lungs

1988 ◽  
Vol 156 (2) ◽  
pp. 619-627 ◽  
Author(s):  
Hiroaki Matsubara ◽  
Yasukiyo Mori ◽  
Yukihisa Umeda ◽  
Shinzo Oikawa ◽  
Hiroshi Nakazato ◽  
...  
Keyword(s):  
Gene Expression ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Rat Lungs ◽  
Peptide Gene ◽  
Atrial Natriuretic

scholarly journals Multiple plasma proteins control atrial natriuretic peptide (ANP) aggregation

2004 ◽  
Vol 33 (2) ◽  
pp. 335-341 ◽  
Author(s):  
C Torricelli ◽  
E Capurro ◽  
A Santucci ◽  
A Paffetti ◽  
C D’Ambrosio ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Mass Spectrometry Analysis ◽  
High Density Lipoproteins ◽  
Protective Mechanism ◽  
Two Dimensional Gel Electrophoresis ◽  
Spectrometry Analysis ◽  
Dimeric Form ◽  
Atrial Natriuretic

We have recently demonstrated that human α-atrial natriuretic peptide (α-hANP), an amyloidogenic peptide responsible for isolated atrial amyloidosis, binds to a dimeric form of apo A-I belonging to small high-density lipoproteins (HDL). This binding phenomenon is considered a protective mechanism since it inhibits or strongly reduces the ANP aggregation process. The observation that plasma exhibits at least four times greater amyloid inhibitory activity than HDL prompted us to determine whether small HDL are the only ANP plasma-binding factors. After incubation of whole plasma with labelled ANP, the macromolecular complexes were subjected to two-dimensional gel electrophoresis followed by autoradiography. The results presented here provide novel evidence of additional binding proteins, in addition to apo A-I dimer, able to bind ANP in vitro and to prevent its aggregation. The mass spectrometry analysis of the radioactive spots identified them as albumin, α-1 antitrypsin, orosomucoid and apo A-IV-TTR complex. The putative impact of these findings in the amyloidogenic/antiamyloidogenic peptides network is discussed.

Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy

2000 ◽  
Vol 279 (4) ◽  
pp. H1635-H1644 ◽  
Author(s):  
Hiroaki Kodama ◽  
Keiichi Fukuda ◽  
Jing Pan ◽  
Motoaki Sano ◽  
Toshiyuki Takahashi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Atrial Natriuretic Peptide ◽  
Cardiac Hypertrophy ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Janus Kinase ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Extracellular Signal ◽  
Atrial Natriuretic

We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90RSK cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated with leukemia inhibitory factor (LIF). LIF sequentially activated Raf-1, MEK1/2, ERK1/2, and p90RSK. We used PD-98059 (a specific MEK inhibitor), AG-490 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that this cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pathways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increase in [3H]phenylalanine uptake by 54.7, 21.5, and 25.6%, respectively, and inhibited the increase in cell area by 61.2, 42.8, and 39.2%, respectively. Reorganization of myofilaments was predominantly suppressed by AG-490. LIF-induced expression of c- fos, brain natriuretic peptide, and skeletal α-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly suppressed by AG-490. These findings indicate that this pathway is critically involved in protein synthesis, induction of c- fos, brain natriuretic peptide, and skeletal α-actin expression and is partially involved in myofilament reorganization and atrial natriuretic peptide induction in gp130-mediated cardiac hypertrophy.

Sign in / Sign up

Export Citation Format

Share Document