scholarly journals Enamel Defects Associated With Dentin Sialophosphoprotein Mutation in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Tian Liang ◽  
Qian Xu ◽  
Hua Zhang ◽  
Suzhen Wang ◽  
Thomas G. H. Diekwisch ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Tooth Development ◽  
Mrna Level ◽  
Extracellular Matrix Protein ◽  
Maturation Stage ◽  
Wild Type ◽  
Micro Computed Tomography ◽  
Enamel Defects ◽  
Dentin Sialophosphoprotein ◽  
Sem Analyses

Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts during tooth development. We previously generated a knockin mouse model expressing a mouse equivalent (DSPP, p.P19L) of human mutant DSPP (p.P17L; referred to as “DsppP19L/+”), and reported that DsppP19L/+ and DsppP19L/P19L mice manifested a dentin phenotype resembling human dentinogenesis imperfecta (DGI). In this study, we analyzed pathogenic effects of mutant P19L-DSPP on enamel development in DsppP19L/+ and DsppP19L/P19L mice. Micro-Computed Tomography (μCT) analyses of 7-week-old mouse mandibular incisors showed that DsppP19L/P19L mice had significantly decreased enamel volume and/or enamel density at different stages of amelogenesis examined. Acid-etched scanning electron microscopy (SEM) analyses of mouse incisors demonstrated that, at the mid-late maturation stage of amelogenesis, the enamel of wild-type mice already had apparent decussating pattern of enamel rods, whereas only minute particulates were found in DsppP19L/+ mice, and no discernible structures in DsppP19L/P19L mouse enamel. However, by the time that incisor enamel was about to erupt into oral cavity, distinct decussating enamel rods were evident in DsppP19L/+ mice, but only poorly-defined enamel rods were revealed in DsppP19L/P19L mice. Moreover, μCT analyses of the mandibular first molars showed that DsppP19L/+ and DsppP19L/P19L mice had a significant reduction in enamel volume and enamel density at the ages of 2, 3, and 24weeks after birth. Backscattered and acid-etched SEM analyses revealed that while 3-week-old DsppP19L/+ mice had similar pattern of enamel rods in the mandibular first molars as age-matched wild-type mice, no distinct enamel rods were observed in DsppP19L/P19L mice. Yet neither DsppP19L/+ nor DsppP19L/P19L mice showed well-defined enamel rods in the mandibular first molars by the age of 24weeks, as judged by backscattered and acid-etched SEM. In situ hybridization showed that DSPP mRNA level was markedly reduced in the presecretory ameloblasts, but immunohistochemistry revealed that DSP/DSPP immunostaining signals were much stronger within the presecretory ameloblasts in Dspp mutant mice than in wild-type mice. These results suggest that mutant P19L-DSPP protein caused developmental enamel defects in mice, which may be associated with intracellular retention of mutant DSPP in the presecretory ameloblasts.

scholarly journals Mutant Dentin Sialophosphoprotein Causes Dentinogenesis Imperfecta

2019 ◽  
Vol 98 (8) ◽  
pp. 912-919 ◽  
Author(s):  
T. Liang ◽  
H. Zhang ◽  
Q. Xu ◽  
S. Wang ◽  
C. Qin ◽  
...  
Keyword(s):  
Dental Pulp ◽  
Matrix Protein ◽  
Mutant Mice ◽  
Extracellular Matrix Protein ◽  
Dentinogenesis Imperfecta ◽  
Wild Type ◽  
Pulp Chamber ◽  
Dentin Sialophosphoprotein ◽  
In The Wild

Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein highly expressed by odontoblasts in teeth. DSPP mutations in humans may cause dentinogenesis imperfecta (DGI), an autosomal dominant dentin disorder. We recently generated a mouse model (named “ DsppP19L/+ mice”) that expressed a mutant DSPP in which the proline residue at position 19 was replaced by a leucine residue. We found that the DsppP19L/+ and DsppP19L/P19L mice at a younger age displayed a tooth phenotype resembling human DGI type III characterized by enlarged dental pulp chambers, while the teeth of older DsppP19L/+ and DsppP19L/P19L mice had smaller dental pulp chambers mimicking DGI type II. The teeth of DsppP19L/+ and DsppP19L/P19L mice had a narrower pulp chamber roof predentin layer, thinner pulp chamber roof dentin, and thicker pulp chamber floor dentin. In addition, these mice also had increased enamel attrition, accompanied by excessive deposition of peritubular dentin. Immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction analyses showed that the odontoblasts in both DsppP19L/+ and DsppP19L/P19L mice had reduced DSPP expression, compared to the wild-type mice. We also observed that the levels of DSPP expression were much higher in the roof-forming odontoblasts than in the floor-forming odontoblasts in the wild-type mice and mutant mice. Moreover, immunohistochemistry showed that while the immunostaining signals of dentin sialoprotein (N-terminal fragment of DSPP) were decreased in the dentin matrix, they were remarkably increased in the odontoblasts of the DsppP19L/+ and DsppP19L/P19L mice. Consistently, our in vitro studies showed that the secretion of the mutant DSPP was impaired and accumulated within endoplasmic reticulum. These findings suggest that the dental phenotypes of the mutant mice were associated with the intracellular retention of the mutant DSPP in the odontoblasts of the DSPP-mutant mice.

Lif Deficiency Leads to Iron Transportation Dysfunction in Ameloblasts

2021 ◽  
pp. 002203452110119
Author(s):  
L. Fan ◽  
Y.J. Ou ◽  
Y.X. Zhu ◽  
Y.D. Liang ◽  
Y. Zhou ◽  
...  
Keyword(s):  
Tooth Development ◽  
Iron Status ◽  
Acid Resistance ◽  
Blue Staining ◽  
Maturation Stage ◽  
Wild Type ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stem Cell Pluripotency ◽  
Underlying Mechanisms

Leukemia inhibitory factor (LIF), a member of the interleukin 6 family of cytokines, is involved in skeletal metabolism, blastocyst implantation, and stem cell pluripotency maintenance. However, the role of LIF in tooth development needs to be elucidated. The aim of the present study was to investigate the effect of Lif deficiency on tooth development and to elucidate the functions of Lif during tooth development and the underlying mechanisms. First, it was found that the incisors of Lif-knockout mice had a much whiter color than those of wild-type mice. Although there were no structural abnormalities or defective mineralization according to scanning electronic microscopy and computed tomography analysis, 3-dimensional images showed that the length of incisors was shorter in Lif−/− mice. Microhardness and acid resistance assays showed that the hardness and acid resistance of the enamel surface of Lif−/− mice were decreased compared to those of wild-type mice. In Lif−/− mice, whose general iron status was comparable to that of the control mice, the iron content of the incisors was significantly reduced, as confirmed by energy-dispersive X-ray spectroscopy (EDS) and Prussian blue staining. Histological staining showed that the cell length of maturation-stage ameloblasts was shorter in Lif−/− mice. Likewise, decreased expression of Tfrc and Slc40a1, both of which are crucial proteins for iron transportation, was observed in Lif−/− mice and Lif-knockdown ameloblast lineage cell lines, according to quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Moreover, the upregulation of Tfrc and Slc40a1 induced by Lif stimulation was blocked by Stattic, a signal transducer and activator of transcription 3 (Stat3) signaling inhibitor. These results suggest that Lif deficiency inhibits iron transportation in the maturation-stage ameloblasts, and Lif modulates expression of Tfrc and Slc40a1 through the Stat3 signaling pathway during enamel development.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms

2016 ◽  
Vol 310 (11) ◽  
pp. H1486-H1493 ◽  
Author(s):  
Teresa Palao ◽  
Catarina Rippe ◽  
Henk van Veen ◽  
Ed VanBavel ◽  
Karl Swärd ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Matrix Protein ◽  
Pressure Overload ◽  
Aortic Aneurysms ◽  
Endoplasmic Reticulum Stress Response ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Wild Type ◽  
Resistance Arteries ◽  
Thrombospondin 4

Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout ( Thbs4 −/−) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4 −/− mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4 −/− mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4 −/− mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4 −/− mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.

scholarly journals Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity

2013 ◽  
Vol 305 (6) ◽  
pp. F871-F880 ◽  
Author(s):  
Wenpeng Cui ◽  
Hasiyeti Maimaitiyiming ◽  
Xinyu Qi ◽  
Heather Norman ◽  
Shuxia Wang
Keyword(s):  
Mouse Model ◽  
Renal Dysfunction ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Diseases ◽  
Extracellular Matrix Protein ◽  
Obese Mouse ◽  
Wild Type ◽  
Thrombospondin 1

Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-β signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-β1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.

Abstract P139: Genetic Signature Of Accelerated Cardiac Fibrosis Due To Trpa1 Ablation

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Shuangtao Ma ◽  
Donna Wang
Keyword(s):  
Matrix Metalloproteinases ◽  
Matrix Protein ◽  
Cardiac Fibrosis ◽  
Collagen Fibers ◽  
Extracellular Matrix Protein ◽  
Myocardial Tissue ◽  
Mrna Levels ◽  
Wild Type ◽  
Genetic Signature ◽  
Age Related

While our previous study demonstrated that loss of transient receptor potential ankyrin 1 ( Trpa1 ) accelerates age-related cardiac fibrosis in mice, the underlying mechanism of potential anti-fibrotic property of TRPA1 remains largely unknown. TRPA1 is a sensor of oxidative stress and may play a protective role in age-related diseases. In this study, we performed quantitative polymerase chain reaction array analyses of the mRNA expression of 84 fibrosis-related genes in the myocardial tissue of 12-month-old Trpa1 -/- mice with significant cardiac fibrosis and age-matched wild-type mice without cardiac fibrosis. The mRNA levels of Col1a2 and Col3a1 in the myocardial tissue were similar between Trpa1 -/- and wild-type mice, suggesting comparable cardiac collagen synthesis in the two strains. Matrix metalloproteinases are major enzymes responsible for degradation of collagen fibers. The results show that the mRNA levels of matrix metalloproteinases, including Mmp1a , Mmp2 , Mmp3 , Mmp8 , Mmp9 , Mmp13 , and Mmp14 , in the heart were similar between Trpa1 -/- and wild-type mice. Nevertheless, we identified 7 significantly changed genes in the heart between the two strains. The expression levels of Acta2 , Inhbe , Ifng , and Ccl11 were significantly increased with fold changes of 3.1, 1.9, 1.9, and 1.5 (all P < 0.05), respectively, while Timp3 , Stat6 , and Ilk were significantly decreased with fold changes of 0.3, 0.5, and 0.7 (all P < 0.05), respectively, in the heart of Trpa1 -/- mice compared with wild-type mice. Acta2 , the most upregulated gene in Trpa1 -/- hearts, is a marker of myofibroblasts. Its upregulation indicates increased differentiation from fibroblasts into myofibroblasts in Trpa1 -/- hearts compared with wild-type hearts. Timp3 , the most downregulated gene in Trpa1 -/- hearts, codes an extracellular matrix protein TIMP3, which not only inhibits matrix metalloproteinases but also regulate post-translational modification of collagen fibers. Taken together, these findings suggest that upregulation of Acta2 and downregulation of Timp3 may serve as genetic signature or play a role in accelerated age-related cardiac fibrosis due to TRPA1 ablation.

Msx1 controls inductive signaling in mammalian tooth morphogenesis

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3035-3044 ◽  
Author(s):  
Y. Chen ◽  
M. Bei ◽  
I. Woo ◽  
I. Satokata ◽  
R. Maas
Keyword(s):  
Matrix Protein ◽  
Tooth Development ◽  
Molar Tooth ◽  
Extracellular Matrix Protein ◽  
Msx Genes ◽  
Tooth Morphogenesis ◽  
Tooth Germs ◽  
Vertebrate Organogenesis ◽  
Inductive Signaling

Members of the Msx homeobox family are thought to play important roles in inductive tissue interactions during vertebrate organogenesis, but their precise developmental function has been unclear. Mice deficient for Msx1 exhibit defects in craniofacial development and a failure of tooth morphogenesis, with an arrest in molar tooth development at the E13.5 bud stage. Because of its potential for experimental manipulation, the murine molar tooth germ provides a powerful system for studying the role of Msx genes in inductive signaling during organogenesis. To further analyze the role of Msx1 in regulating epithelial-mesenchymal interactions during tooth morphogenesis, we have examined the expression of several potential Msx1 downstream genes in Msx1 mutant tooth germs and we have performed functional experiments designed to order these genes into a pathway. Our results show that expression of Bone Morphogenetic Protein 4 (BMP4), the HMG box gene Lef1 and the heparan sulfate proteoglycan syndecan-1 is specifically reduced in Msx1 mutant dental mesenchyme, while expression of the extracellular matrix protein tenascin is unaffected. BMP4 soaked beads can induce Bmp4 and Lef1 expression in explanted wild-type dental mesenchymes, but only Lef1 expression in Msx1 mutant dental mesenchyme. We thus conclude that epithelial BMP4 induces its own expression in dental mesenchyme in a manner that requires Msx1. In turn, we show that addition of BMP4 to Msx1 deficient tooth germs bypasses the requirement for Msx1 and rescues epithelial development from the bud stage to the E14.5 cap stage. Lastly, we show that FGFs induce syndecan-1 expression in dental mesenchyme in a manner that also requires Msx-1. These results integrate Msx1 into a regulatory hierarchy in early tooth morphogenesis and demonstrate that Msx1 is not only expressed in dental mesenchyme in response to epithelial signals, but also in turn regulates the reciprocal expression of inductive signals in the mesenchyme which then act back upon the dental epithelium. We propose that Msx genes function repetitively during vertebrate organogenesis to permit inductive signaling to occur back and forth between tissue layers.

scholarly journals Major Surface Protein LipL32 Is Not Required for Either Acute or Chronic Infection with Leptospira interrogans

2008 ◽  
Vol 77 (3) ◽  
pp. 952-958 ◽  
Author(s):  
Gerald L. Murray ◽  
Amporn Srikram ◽  
David E. Hoke ◽  
Elsio A. Wunder ◽  
Rebekah Henry ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Chronic Infection ◽  
Matrix Protein ◽  
Severe Disease ◽  
Extracellular Matrix Protein ◽  
Leptospira Interrogans ◽  
Renal Tubules ◽  
Wild Type

ABSTRACT Leptospira interrogans is responsible for leptospirosis, a zoonosis of worldwide distribution. LipL32 is the major outer membrane protein of pathogenic leptospires, accounting for up to 75% of total outer membrane protein. In recent times LipL32 has become the focus of intense study because of its surface location, dominance in the host immune response, and conservation among pathogenic species. In this study, an lipL32 mutant was constructed in L. interrogans using transposon mutagenesis. The lipL32 mutant had normal morphology and growth rate compared to the wild type and was equally adherent to extracellular matrix. Protein composition of the cell membranes was found to be largely unaffected by the loss of LipL32, with no obvious compensatory increase in other proteins. Microarray studies found no obvious stress response or upregulation of genes that may compensate for the loss of LipL32 but did suggest an association between LipL32 and the synthesis of heme and vitamin B12. When hamsters were inoculated by systemic and mucosal routes, the mutant caused acute severe disease manifestations that were indistinguishable from wild-type L. interrogans infection. In the rat model of chronic infection, the LipL32 mutant colonized the renal tubules as efficiently as the wild-type strain. In conclusion, this study showed that LipL32 does not play a role in either the acute or chronic models of infection. Considering the abundance and conservation of LipL32 among all pathogenic Leptospira spp. and its absence in saprophytic Leptospira, this finding is remarkable. The role of this protein in leptospiral biology and pathogenesis thus remains elusive.

Experimental Inhibition of Periostin Attenuates Kidney Fibrosis

2017 ◽  
Vol 46 (6) ◽  
pp. 501-517 ◽  
Author(s):  
Jin Ho Hwang ◽  
Seung Hee Yang ◽  
Yong Chul Kim ◽  
Jin Hyuk Kim ◽  
Jung Nam An ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Matrix Protein ◽  
Collecting Duct ◽  
Extracellular Matrix Protein ◽  
In Vitro Experiments ◽  
Wild Type ◽  
In The Wild ◽  
Renal Fibrogenesis

Background: Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis. Methods: We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used. Results: Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, α-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-β signaling and the inflammatory and apoptotic pathways. Conclusion: Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression.

scholarly journals Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knock-out, and LacZ knock-in mice

2020 ◽  
Author(s):  
Hoyun Kwak ◽  
Eun-Ho Cho ◽  
Eun Bee Cho ◽  
Yoo-Na Lee ◽  
Anu Shahapal ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Hek293 Cells ◽  
Extracellular Matrix Protein ◽  
Dependent Manner ◽  
Wild Type ◽  
Adipose Tissues ◽  
Peripheral Tissues ◽  
Knock Out ◽  
Protein Levels ◽  
The Brain

AbstractFAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligand-mediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.

Abstract 11021: Circulating Cardiac Transforming Growth Factor-β is a Principal Determinant in Inducing Myocardial Hypertrophy in Transgenic Mice Overexpressing Exogenous Hepatic Transforming Growth Factor-β

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shaukat A Khan ◽  
Takeshi Tsuda
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Myocardial Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Potent Growth

Introduction: Transforming growth factor (TGF)-β is a potent growth factor that induces myocardial hypertrophy, but an interaction between circulating and myocardial TGF-β has been poorly understood. An extracellular matrix protein, fibulin-2, mediates exogenous TGF-β-induced endogenous TGF-β up-regulation in isolated cardiac fibroblasts. Hypothesis: Systemic TGF-β-induced myocardial hypertrophy is mediated primarily by enhanced myocardial TGF-β via paracrine fashion. Methods: We created double mutant mice with TGF-β1 over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG developed myocardial hypertrophy due to excessive circulating hepatic TGF-β. We studied TGF-β dynamics between tissues and circulation during hypertrophic changes. Results: TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in TG/KO was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA level was significantly up-regulated in TG/WT compared with TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity was no different among all four groups. Serum carrier-bound TGF-β was significantly higher in TG/WT than in TG/KO or NTG groups, but free unbound TGF-β level was equally elevated in TG groups compared with NTG groups. Thus, hypertrophy in TG/WT may be attributed to increased serum carrier-bound TGF-β levels, not to either myocardial TGF-β activity or serum unbound TGF-β levels. Endogenous TGF-β mRNA level in kidney and liver was equally increased in TG group compared with NTG group, and was comparable in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in kidney, liver, or lung. Conclusions: Hepatic TGF-β-induced-myocardial TGF-β up-regulation was mediated by fibulin-2. In TG/WT, up-regulated myocardial TGF-β was mainly secreted into circulation as a soluble carrier-bound form and did not directly induce hypertrophy via paracrine fashion. It is this circulating endogenous myocardial TGF-β rather than transgene-induced hepatic TGF-β that is responsible for myocardial hypertrophy in TG/WT. Heart is a major endocrine organ in secreting circulating endogenous TGF-β in inducing myocardial hypertrophy.

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