Abstract 78: Transforming Growth Factor-β Induces the Cardiac Fibrosis and Remodeling in Guanylyl cyclase/Natriuretic Peptide Receptor-A Gene-Disrupted Null Mutant Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kailash N Pandey ◽  
Umadevi Subramanian
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Null Mutant ◽  
Wild Type ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Β Receptor ◽  
Null Mutant Mice

Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) in mice exhibits high blood pressure, cardiac hypertrophy, fibrosis, and remodeling leading to congestive heart failure. The objective of this study was to determine the mechanisms regulating the development of fibrosis in Npr1 gene-disrupted mice hearts. The Npr1 null mutant (Npr1-/-, 0-copy), heterozygous (Npr1+/-, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were administered by oral gavage with transforming growth factor-β1 (TGF- β1) receptor inhibitor GW788388 (1mg/kg/day) for 28 days. The heart tissues were isolated and used for quantification of fibrotic markers by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analyses. Together, systolic blood pressure (SBP), heart weight-to-body weight (HW/BW) ratio, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), and percent fractional shortening (FS) were analyzed. The Npr1-/- null mutant mice hearts displayed 6-fold induction of fibrosis compared with wild-type (WT) Npr1+/+ mice. Furthermore, the increased expression of fibrotic markers as observed, including connective tissue growth factor (CTGF, 5-fold), α-smooth muscle actin (α-SMA, 4-fold) and TGF-β receptor I (TGF-βRI, 4-fold), TGF-β receptor II (TGF-βRII, 3.5-fold) and Smad2/3 proteins in Npr1-/- mice hearts compared with WT control mice. However, treatment with TGF-β receptor antagonist, GW788388, significantly prevented the cardiac fibrosis and down-regulated the expression of fibrotic markers and Smad proteins in Npr1-/- mice compared to vehicle-treated WT controls. The results of the present study suggest that the activation of cardiac fibrosis in Npr1-/- mice is mainly triggered through TGF-β mediated Smad-dependent pathways.

Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Chandramohan Ramasamy ◽  
Umadevi Subramanian ◽  
Kailash N Pandey
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Growth Factor ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p<0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p<0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p<0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

The Liver in Transforming Growth Factor-Beta-1 (TGF-β1) Null Mutant Mice

1996 ◽  
Vol 20 (5) ◽  
pp. 477-490 ◽  
Author(s):  
A. Olufemi Williams ◽  
Alan D. Knapton ◽  
Andrew Geiser ◽  
John J. Letterio ◽  
Anita B. Roberts
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mutant Mice ◽  
Null Mutant ◽  
Growth Factor Beta ◽  
Null Mutant Mice ◽  
Tgf Β1

Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice

2009 ◽  
Vol 21 (4) ◽  
pp. 561 ◽  
Author(s):  
Leanne J. McGrath ◽  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Sarah A. Robertson
Keyword(s):  
Growth Factor ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Mating Behaviour ◽  
Bovine Milk ◽  
Reproductive Function ◽  
Serum Testosterone ◽  
Mutant Mice ◽  
Null Mutant ◽  
Null Mutant Mice

Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor β1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (~150 μg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.

scholarly journals Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

2001 ◽  
Vol 276 (50) ◽  
pp. 47483-47488 ◽  
Author(s):  
Kazuhiro Ishiguro ◽  
Kenji Kadomatsu ◽  
Tetsuhito Kojima ◽  
Hisako Muramatsu ◽  
Mitsunori Iwase ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Mortality ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Endotoxin Shock ◽  
Left Ventricular ◽  
Wild Type ◽  
In The Wild ◽  
Deficient Mice ◽  
Fractional Shortening

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1β was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1β was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-β1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-β1 on IL-1β production.

301. Effect of exogenous transforming growth factor beta 1 on reproductive performance in male TGFβ1 null mice

2005 ◽  
Vol 17 (9) ◽  
pp. 128
Author(s):  
L. J. McGrath ◽  
R. Robker ◽  
S. A. Robertson
Keyword(s):  
Growth Factor ◽  
Reproductive Performance ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mating Behaviour ◽  
Mutant Mice ◽  
Null Mutant ◽  
Exogenous Cytokine ◽  
Growth Factor Beta ◽  
Null Mutant Mice

The transforming growth factor beta 1 (TGFβ1) family are potent cytokines that regulate tissue development, inflammation and immunity. Our studies in null mutant mice implicate a key role for TGFβ1 in male reproductive function. The TGFβ1 null mutation results in profound infertility due to inability to copulate successfully associated with reduced testosterone synthesis, although penile erection and sperm production do occur. To investigate whether fertility status can be improved in TGFβ1 null mutant mice by exogenous cytokine replacement, we used Alzet mini-pumps implanted subcutaneously to deliver a constant supply of recombinant latent TGFβ1 to TGFβ–/– mice (n = 7, 2.1µg/day over 2 weeks). Control TGFβ–/– mice (n = 6) and +/+ mice (n = 10) received pumps containing BSA carrier only. Circulating levels of TGFß1 were increased in TGFβ–/– mice and reached levels comparable to those seen in fertile heterozygote littermates. Increased circulating testosterone was evident in a proportion of TGFβ–/– mice after exogenous TGFβ replacement compared with untreated control mice. However, serum testosterone content was widely variable within all groups, so statistical significance was not achieved. Videotaping of nocturnal mating behaviour while caging treated males with normal receptive female mice showed that unlike TGFβ+/+ mice, which successfully mounted and intromitted, untreated TGFβ–/– mice failed to engage in normal mating behaviour. TGFβ–/– mice treated with exogenous cytokine were occasionally seen to intromit but less frequently than TGFβ+/+ controls. Ejaculation did not occur in any of the TGFβ–/– mice regardless of TGFβ replacement, compared with TGFβ+/+ mice where 8/10 mice ejaculated during the 2 h observation period. The trend towards improvement in both testosterone levels and copulation activity of the TGFβ1 null mice treated with exogenous cytokine suggests that systemic TGFβ1 availability may influence reproductive performance in male mice. However, since fertility was not restored by cytokine replacement, locally produced TGFβ in the reproductive tract and/or hypothalamic pituitary axis are also implicated in regulating fertility.

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