scholarly journals Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

2006 ◽  
Vol 103 (12) ◽  
pp. 4735-4740 ◽  
Author(s):  
T. H. Langenickel ◽  
J. Buttgereit ◽  
I. Pagel-Langenickel ◽  
M. Lindner ◽  
J. Monti ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Natriuretic Peptide Receptor ◽  
Transgenic Rats ◽  
Peptide Receptor ◽  
Negative Mutant

Abstract 189: Natriuretic Peptide Receptor-A Regulates Angiotensin-II Mediated NF-κB Via Mkp-1 Dependent Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Gopi Venkatachalam ◽  
Umadevi Subramanian ◽  
Parthasarathy Arumugam ◽  
Elangovan Vellaichamy
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Nuclear Translocation ◽  
Heart Tissue ◽  
Male Rats ◽  
Natriuretic Peptide Receptor ◽  
Ang Ii ◽  
Hypertrophic Growth ◽  
Peptide Receptor

Atrial natriuretic peptide (ANP) exerts local anti-hypertrophic activity in heart tissue by binding to natriuretic peptide receptor (NPR)-A. However, patients with cardiac hypertrophy and congestive heart failure have elevated plasma and tissue levels of ANP and brain natriuretic peptide (BNP) along with Angiotensin II (Ang II). However, the rationale behind the impaired action of ANP in diseased state is not well understood. In this study, we sought to examine the signaling mechanism by which Ang II modulates local anti-hypertrophic effect through inhibition of Npr1 gene, which codes for NPR-A, in the heart. Hence, in vivo , Wistar male rats (n=8/group) were administered suppressor dose of Ang II (50ng/kg/min) for 14 days through implanted mini-osmotic pumps. Also, in vitro , H9C2 (2-1) cardio myofibroblast cells were exposed to Ang II (10 -7 M) for 20 hours. Upon treatment with Ang II, the mRNA and protein expression of Npr1 (p<0.01) was decreased with significant increase in expression of AT1R (p<0.01) in the heart tissues. In addition, a concomitant decrease in cGMP activity and production in isolated heart tissue membrane preparation was found in Ang II infused rats. Moreover, Ang II infusion causes a suppression of MKP-1 phosphatase; while enhancing the phosphorylation of ERK1/2 (p<0.01) and NF-κB (p<0.01) proteins. Similarly, H9C2 cells exhibited the hypertrophic growth with increased expression of AT1R and activation of ERK1/2 proteins on stimulation with Ang II. Furthermore, gene silencing using siRNA-NPR-A prior to Ang II treatment augmented the translocation of NF-κB and activation of ERK1/2 (3-fold). Whereas, pre-treatment with losartan or cGMP analog 8-Br-cGMP, an activator of cGMP-dependent protein kinases, abolished the stimulatory effects of Ang II on AT1R, NF-κB nuclear translocation and phosphorylation of MAPK, but activated the MKP-1 phosphatase. These results suggest that NPRA-cGMP signaling exerts inhibitory effects on Ang II by antagonizing the upstream signaling pathways and by activation of MKP-1 to counter-regulate NF-κB and MAPKs through cGMP dependent mechanism; thereby mediate local anti-hypertrophic activity in cardiac hypertrophy.

NF-κB activation is required for the development of cardiac hypertrophy in vivo

2004 ◽  
Vol 287 (4) ◽  
pp. H1712-H1720 ◽  
Author(s):  
Yuehua Li ◽  
Tuanzhu Ha ◽  
Xiang Gao ◽  
Jim Kelley ◽  
David L. Williams ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Weight Ratio ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Mutant ◽  
Body Weight Ratio ◽  
Aortic Banding ◽  
Important Target

In the present study, we examined whether NF-κB activation is required for cardiac hypertrophy in vivo. Cardiac hypertrophy in rats was induced by aortic banding for 1, 3, and 5 days and 1–6 wk, and age-matched sham-operated rats served as controls. In a separate group of rats, an IκB-α dominant negative mutant (IκB-αM), a superrepressor of NF-κB activation, or pyrrolidinedithiocarbamate (PDTC), an antioxidant that can inhibit NF-κB activation, was administered to aortic-banded rats for 3 wk. The heart weight-to-body weight ratio was significantly increased at 5 days after aortic banding, peaked at 4 wk, and remained elevated at 6 wk compared with age-matched sham controls. Atrial natriuretic peptide and brain natriuretic peptide mRNA expressions were significantly increased after 1 wk of aortic banding, reached a maximum between 2 and 3 wk, and remained increased at 6 wk compared with age-matched sham controls. NF-κB activity was significantly increased at 1 day, reached a peak at 3 wk, and remained elevated at 6 wk, and IKK-β activity was significantly increased at 1 day, peaked at 5 days, and then decreased but remained elevated at 6 wk after aortic banding compared with age-matched sham controls. Inhibiting NF-κB activation in vivo by cardiac transfection of IκB-αM or by PDTC treatment significantly attenuated the development of cardiac hypertrophy in vivo with a concomitant decrease in NF-κB activity. Our results suggest that NF-κB activation is required for the development of cardiac hypertrophy in vivo and that NF-κB could be an important target for inhibiting the development of cardiac hypertrophy in vivo.

scholarly journals Connexin 32 dominant-negative mutant transgenic rats are resistant to hepatic damage by chemicals

Hepatology ◽  
2004 ◽  
Vol 40 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Makoto Asamoto ◽  
Naomi Hokaiwado ◽  
Toshiya Murasaki ◽  
Tomoyuki Shirai
Keyword(s):  
Dominant Negative ◽  
Hepatic Damage ◽  
Dominant Negative Mutant ◽  
Connexin 32 ◽  
Transgenic Rats ◽  
Negative Mutant

scholarly journals Phosphorylation of the Kinase Homology Domain Is Essential for Activation of the A-Type Natriuretic Peptide Receptor

1998 ◽  
Vol 18 (4) ◽  
pp. 2164-2172 ◽  
Author(s):  
Lincoln R. Potter ◽  
Tony Hunter
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Cyclase Activity ◽  
Atp Binding ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Kinase Homology Domain ◽  
Kinase Homology

ABSTRACT Natriuretic peptide receptor A (NPR-A) is the biological receptor for atrial natriuretic peptide (ANP). Activation of the NPR-A guanylyl cyclase requires ANP binding to the extracellular domain and ATP binding to a putative site within its cytoplasmic region. The allosteric interaction of ATP with the intracellular kinase homology domain (KHD) is hypothesized to derepress the carboxyl-terminal guanylyl cyclase catalytic domain, resulting in the synthesis of the second messenger, cyclic GMP. Here, we show that phosphorylation of the KHD is essential for receptor activation. Using a combination of phosphopeptide mapping techniques, we have identified six residues within the ATP-binding domain (S497, T500, S502, S506, S510, and T513) which are phosphorylated when NPR-A is expressed in HEK 293 cells. Mutation of any one of these Ser or Thr residues to Ala caused reductions in the receptor phosphorylation state, the number and pattern of phosphopeptides observed in tryptic maps, and ANP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in NPR-A protein levels, as indicated by immunoblot analysis and determinations of cyclase activity in the presence of detergent. Conversion of Ser-497 to Ala resulted in the most dramatic decrease in cyclase activity (∼20% of wild-type activity), but conversion to an acidic residue (Glu), which mimics the charge of the phosphoserine moiety, had no effect. Simultaneous mutation of five of the phosphorylation sites to Ala resulted in a dephosphorylated receptor which was unresponsive to hormone and had potent dominant negative inhibitory activity. We conclude that phosphorylation of the KHD is absolutely required for hormone-dependent activation of NPR-A.

scholarly journals Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

2001 ◽  
Vol 107 (8) ◽  
pp. 975-984 ◽  
Author(s):  
Joshua W. Knowles ◽  
Giovanni Esposito ◽  
Lan Mao ◽  
John R. Hagaman ◽  
Jennifer E. Fox ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Pressure Independent ◽  
Deficient Mice

scholarly journals Influence of natriuretic peptide receptor-1 on survival and cardiac hypertrophy during development

2009 ◽  
Vol 1792 (12) ◽  
pp. 1175-1184 ◽  
Author(s):  
Nicola J.A. Scott ◽  
Leigh. J. Ellmers ◽  
John G. Lainchbury ◽  
Nobuyo Maeda ◽  
Oliver Smithies ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor

Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

2006 ◽  
Vol 290 (4) ◽  
pp. H1635-H1641 ◽  
Author(s):  
Tue E. H. Christoffersen ◽  
Mark Aplin ◽  
Claes C. Strom ◽  
Soren P. Sheikh ◽  
Ole Skott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Left Ventricle ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Natriuretic Peptide Receptor ◽  
Angiotensin System ◽  
Peptide Receptor

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg·kg−1·day−1) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% ( P < 0.001) and 520% ( P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

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