ANP signaling inhibits TGF-β-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells

Liu, Mingchun; Oparil, Suzanne; Novak, Lea; Cao, Xu; Shi, Weibin; Lucas, Jason; Chen, Yiu Fai

doi:10.1152/japplphysiol.00468.2006

Cited by 57 publications

(51 citation statements)

References 33 publications

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“…12,33,37,38 This assumption is based on the known inhibitory effects of cGMP on collagen synthesis and the TGFb1 pathway, and its vasculoprotective effects on arterial SMC. [14][15][16][17]20,[45][46][47] However, the anti-apoptotic and pro-proliferative effects of sildenafil that we found in the corporal smooth muscle do not agree with the fact that cGMP inhibits vascular SMC proliferation. 48,49 Since the effects of BCNR on the corporal histology and pharmacokinetics are the same as those seen in the aged rat, we assume that cGMP effects on corporal SMC may be modulated by some specific features in the corporal SMC themselves or the tissue milieu, that are not operative in the vascular SMC.…”

Section: Discussioncontrasting

confidence: 91%

“…[11][12][13] It is likely that this occurs through the maintenance of high levels of cGMP, since this compound reduces collagen synthesis and the activation of the pro-fibrotic TGFb1 pathway and protects SMC from apoptosis, while stimulating the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2). [14][15][16][17][18][19][20][21][22][23] The expression of iNOS in certain non-immunological tissues is assumed to be a defense mechanism against fibrosis. [24][25][26][27][28][29] The nitric oxide produced by iNOS, besides inhibiting collagen synthesis and the TGFb1 pathway, also quenches reactive oxygen species, and in some cases, the differentiation of fibroblasts to myofibroblasts, the cells that produce collagen in many fibrotic conditions.…”

Section: Introductionmentioning

confidence: 99%

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Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

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Section: Discussioncontrasting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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“…Larvae subjected to H 2 O 2 and simultaneous PKG drug treatment included one of the following agents dissolved in DMSO (all chemicals obtained from Sigma, St. Louis, MO): 40 M 8-bromo-cGMP; (a PKG activator; Ruth et al 1991), 1 M KT-5823 (a relatively selective, competitive PKG inhibitor; Grider 1993; Kase et al 1987), or 50 M Rp-8-bromo-cGMP (a more selective PKG inhibitor that irreversibly binds to the kinase; Petrov et al 2008;Wei et al 1996). These concentrations were previously shown to alter PKG activity in insect and mammalian models (Dawson-Scully et al 2007;Li et al 2007).…”

Section: Methodsmentioning

confidence: 94%

A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction

Caplan

Milton

2013

Journal of Neurophysiology

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“…Northern blot analysis for PAI-1 and GAPDH (internal control) mRNA levels was performed. 1,12 Effects of ANP/cGMP on TGF-␤1-Induced…”

Section: Effects Of Anp On Cgmp Levels and Effects Of Anp/cgmp On Colmentioning

confidence: 99%

Atrial Natriuretic Peptide Inhibits Transforming Growth Factor β–Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts

Liu

Wang

Lucas

et al. 2008

Circulation Research

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191

136

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Abstract-This study tested the hypothesis that activation of atrial natriuretic peptide (ANP)/cGMP/protein kinase G signaling inhibits transforming growth factor (TGF)-␤1-induced extracellular matrix expression in cardiac fibroblasts and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Left ventricular hypertrophy and fibrosis, collagen deposition, and myofibroblast transformation of cardiac fibroblasts in response to pressure overload by transverse aortic constriction were exaggerated in ANP-null mice compared with wild-type controls. ANP and cGMP inhibited TGF-␤1-induced myofibroblast transformation, proliferation, collagen synthesis, and plasminogen activator inhibitor-1 expression in cardiac fibroblasts isolated from wild-type mice. Following pretreatment with cGMP, TGF-␤1 induced phosphorylation of Smad3, but the resultant pSmad3 could not be translocated to the nucleus. pSmad3 that had been phosphorylated with recombinant protein kinase G-1␣ was analyzed by use of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and ion trap tandem mass spectrometry. The analysis revealed phosphorylation of Ser309 and Thr388 residues, sites distinct from the C-terminal Ser423/425 residues that are phosphorylated by TGF-␤ receptor kinase and are critical for the nuclear translocation and down-stream signaling of pSmad3. These results suggest that phosphorylation of Smad3 by protein kinase G is a potential molecular mechanism by which activation of ANP/cGMP/protein kinase G signaling disrupts TGF-␤1-induced nuclear translocation of pSmad3 and downstream events, including myofibroblast transformation, proliferation, and expression of extracellular matrix molecules in cardiac fibroblasts. We postulate that this process contributes to the antifibrogenic effects of the natriuretic peptide in heart. (Circ Res. 2008;102:185-192.)

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ANP signaling inhibits TGF-β-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells

Cited by 57 publications

References 33 publications

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction

Atrial Natriuretic Peptide Inhibits Transforming Growth Factor β–Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts

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