scholarly journals Sex-specific regulation of collagen I and III expression by 17β-Estradiol in cardiac fibroblasts: role of estrogen receptors

2018 ◽  
Vol 115 (2) ◽  
pp. 315-327 ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Cindy Schriever ◽  
Kana Kusumoto ◽  
Lisa Kramer ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Collagen I ◽  
Female Rat ◽  
17Β Estradiol ◽  
Specific Regulation

Abstract Aims Sex differences in cardiac fibrosis point to the regulatory role of 17β-Estradiol (E2) in cardiac fibroblasts (CF). We, therefore, asked whether male and female CF in rodent and human models are differentially susceptible to E2, and whether this is related to sex-specific activation of estrogen receptor alpha (ERα) and beta (ERβ). Methods and results In female rat CF (rCF), 24 h E2-treatment (10−8  M) led to a significant down-regulation of collagen I and III expression, whereas both collagens were up-regulated in male rCF. E2-induced sex-specific collagen regulation was also detected in human CF, indicating that this regulation is conserved across species. Using specific ERα- and ERβ-agonists (10−7 M) for 24 h, we identified ERα as repressive and ERβ as inducing factor in female and male rCF, respectively. In addition, E2-induced ERα phosphorylation at Ser118 only in female rCF, whereas Ser105 phosphorylation of ERβ was exclusively found in male rCF. Further, in female rCF we found both ER bound to the collagen I and III promoters using chromatin immunoprecipitation assays. In contrast, in male rCF only ERβ bound to both promoters. In engineered connective tissues (ECT) from rCF, collagen I and III mRNA were down-regulated in female ECT and up-regulated in male ECT by E2. This was accompanied by an impaired condensation of female ECT, whereas male ECT showed an increased condensation and stiffness upon E2-treatment, analysed by rheological measurements. Finally, we confirmed the E2-effect on both collagens in an in vivo mouse model with ovariectomy for E2 depletion, E2 substitution, and pressure overload by transverse aortic constriction. Conclusion The mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERβ signaling in CFs.

Abstract 237: Sex-specific Regulation Of Collagen I And III Expression By 17β-estradiol In Rat Cardiac Fibroblasts: Role Of Estrogen Receptors

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Sandra Kunze ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Sex Differences ◽  
Western Blot ◽  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Collagen I ◽  
Female Rats ◽  
17Β Estradiol ◽  
Specific Regulation

Clinical and animal studies showed in female pressure-overloaded hearts less cardiac fibrosis and collagen I and III gene expression compared to males, suggesting an inhibitory effect of 17β-Estradiol (E2) on collagens. Therefore we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression in isolated rat cardiac fibroblasts from both sexes. Cardiac fibroblasts were isolated from adult male and female Wistar rats, and treated with E2 (10-8M), vehicle, ERα and ERβ-agonist (10-7M) and/or pre-treated with ICI 182,780 (10-5M) for 24h. Cellular localization of ER in cardiac fibroblasts with/without E2 was detected by immunofluorescence staining, and expression of both ER was determined by western blot. Expression of collagen I and III was determined by qRT-PCR and western blot. E2-treatment led to a nuclear translocation of ERα and ERβ in cardiac fibroblasts, suggesting the functional activity of ER as transcription factors. Furthermore in cardiac fibroblasts from female rats E2 led to a significant down-regulation of collagen I and III gene and protein expression. In contrast there was a significant increase of collagen I and III levels in fibroblasts isolated from male rat hearts by E2. E2-effect could be inhibited by ICI 182, 780 indicating the involvement of ER. In cardiac fibroblasts from female rats, ERα-agonist treatment led to a significant down-regulation of collagen I and III mRNA level, but ERβ-agonist had no effects. In contrast, ERβ-agonist treatment of cardiac fibroblasts from males increased collagen I and III mRNA, but no changes with ERα agonist-treatment were detected. ERα protein levels displayed no sex differences at basal level. After E2-treatment ERα protein was up-regulated in male cells, but decreased in cardiac fibroblasts from females. ERβ protein was higher in female cells compared to males, but the expression was not regulated by E2 in both sexes. Sex-specific regulation of collagen I and III expression by E2 in cardiac fibroblasts might be responsible for sex-differences in cardiac fibrosis. This might be due to sexually dimorphic ER expression and regulation. Understanding how E2 and ER mediate sex-differences in cardiac remodeling may help to design sex-specific pharmacological interventions.

Abstract 89: 17beta-Estradiol-activated Estrogen Receptors Attenuate Cardiac Fibrosis Through Inhibition of Collagen I and III Expression in Female Hearts

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Christina Westphal ◽  
Daniela Fliegner ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Collagen I ◽  
Sham Operation ◽  
Female Rat ◽  
Female Mice ◽  
Gene And Protein Expression

Objectives: Female pressure-overloaded hearts show less fibrosis compared with males. 17β-Estradiol (E2) attenuates cardiac fibrosis in female mice. Whether this is mediated by direct E2-effects on collagen synthesis is still unknown. Therefore, we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression and analyzed involved mechanisms. Methods: Female C57BL/6J mice (7 weeks) underwent sham operation, ovariectomy (OVX), OVX with E2-supplementation (390mg E2-containing pellets) or placebo. After 2 weeks, animals underwent transverse aortic constriction (TAC) or sham surgery. Mice were sacrificed after 9 weeks. Collagen amount, collagen I and III protein in left ventricular tissue were detected by Sirius Red and antibody staining, respectively. Gene and protein expression were determined by quantitative Real-Time PCR and Western blot. Adult female rat cardiac fibroblasts were treated with E2 (10 -8 M), vehicle, ERα- and β-agonists (10 -7 M) for 24h or pre-treated with PD98059 for 1h. ER binding to the collagen I and III promoter was analyzed by chromatin immunoprecipitation assays. Findings: In female OVX mice, undergoing TAC surgery, E2-supplementation significantly reduced collagen deposition, collagen I and III mRNA and protein levels in comparison with mice without E2. In female rat cardiac fibroblasts, E2 significantly down-regulated collagen I and III mRNA and protein level. Specific ER-agonist-treatment showed that E2-mediated regulation of collagen I and III expression was mediated via activation of ERα, but not ERβ. Further, upon E2-treatment, ERα was phosphorylated at Ser118, which occurred by E2-induced activation of ERK1/2 signaling. Furthermore, we could show that ERα and ERβ bind to two putative half-palindromic estrogen response elements within the collagen I and III promoter in female cardiac fibroblasts. Conclusion: E2 inhibits cardiac collagen I and III mRNA and protein in female mice under pressure overload. Data from rat female cardiac fibroblasts suggest that this is mediated via E2-activated ERK1/2 signaling and ERα, which binds with ERβ to the collagen I and III promoter. Understanding of how E2/ER attenuate collagen I and III expression in pathological hypertrophy may improve therapy.

Abstract 423: Kinase Independent Signaling of PI3Kγ Mediates Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Maradumane L Mohan ◽  
Lisa M Grove ◽  
Mitchell A Olman ◽  
Sathyamangla V Naga Prasad
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Stress Fibers ◽  
Independent Function ◽  
Specific Expression ◽  
Myofibroblast Phenotype

Phosphoinositide 3 Kinase γ (PI3Kγ) belongs to a family of lipid kinases genetic deletion of which leads to pressure overload induced cardiac fibrosis in mice. However, the mechanism by which PI3Kγ mediates cardiac fibrosis is unknown. Cardiac fibrosis is a key underlying cause of fatal heart failure. A well-known fibrogenic mechanism is the generation of myofibroblasts, which are characterized by overexpression of smooth muscle α-actin (αSMA). Myofibroblast is a fibrosis-effector cell that produces pro-fibrotic cytokines and exuberant extracellular matrix that leads to cardiac fibrosis. To evaluate the role of PI3Kγ in fibrotic phenotype, cardiac tissue lysates from 3 months old WT and PI3Kγ null (PI3Kγ -/- ) mice were assessed for the expression of αSMA. Interestingly, there is significant up-regulation of αSMA in PI3Kγ -/- in comparison to littermate controls (WT) even at baseline suggesting that loss of PI3Kγ predisposes the hearts towards fibrosis. To directly confirm that PI3Kγ -/- cardiac fibroblasts (CF) exhibit a myofibroblast phenotype even at baseline, CF were isolated from hearts of WT and PI3Kγ -/- mice and assessed for myofibroblast phenotype by immunostaining for αSMA in stress fibers. Fluorescence microscopy on the CF from PI3Kγ -/- mice showed intense immunostaining for αSMA with greater number of cells exhibiting αSMA in stress fibers when compared to CF from WT mice. Consistently, immunoblotting showed significantly higher αSMA protein levels in PI3Kγ -/- CF compared to WT CF suggesting that PI3Kγ -/- fibroblasts are “primed” to undergo myofibroblast differentiation. To determine the role of kinase-independent function of PI3Kγ in vivo, we generated unique mice lines with cardiomyocyte-specific expression of either kinase-dead PI3Kγ (PI3Kγ inact ) or constitutively active PI3Kγ ( Myr PI3Kγ) in the global PI3Kγ -/- (PI3Kγ inact /PI3Kγ -/- or Myr PI3Kγ/PI3Kγ -/- ) and measured αSMA. Surprisingly, abundance of αSMA protein is significantly reduced in PI3Kγ inact /PI3Kγ -/- when compared to WT and PI3Kγ -/- mice. These data reveal that kinase-independent function of PI3Kγ is a key component in the myocyte-initiated pathway that ultimately drives CF to become myofibroblasts uncovering a novel mechanism of regulating pro-fibrotic signals.

Abstract 277: Microrna-33 Promotes Cardiac Fibrosis by Maintaining Cellular Lipid Homeostasis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Masataka Nishiga ◽  
Takahiro Horie ◽  
Yasuhide Kuwabara ◽  
Osamu Baba ◽  
Tetsushi Nakao ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Cholesterol Content ◽  
Atp Binding Cassette Transporter ◽  
Primary Fibroblasts ◽  
Proliferation In Vitro ◽  
Altered Lipid

Background: A highly conserved microRNA, miR-33 is considered as a potential therapeutic target for atherosclerosis, because recent reports, including ours, indicated miR-33 has atherogenic effects by reducing HDL-C. However, the functions of miR-33 in heart failure remain to be elucidated. Methods and results: To clarify the functions of miR-33 involved in cardiac hypertrophy and fibrosis in vivo, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33 deficient (KO) mice. When subjected to TAC, miR-33 expression level was significantly up-regulated in wild-type (WT) left ventricles, whereas miR-33 KO hearts displayed no less hypertrophic responses than WT hearts. However, interestingly, histological and gene expression analyses showed ameliorated cardiac fibrosis in miR-33 KO hearts compared to WT hearts. Furthermore, we generated cardiac fibroblast specific miR-33 deficient mice, which also showed ameliorated cardiac fibrosis when they were subjected to TAC. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart, because its expression was about 4-folds higher in isolated primary cardiac fibroblasts than cardiomyocytes. Deficiency of miR-33 impaired cell proliferation in primary fibroblasts, which was considered due to altered lipid raft cholesterol content by up-regulated ATP-binding cassette transporter A1/G1. Conclusion: Deficiency of miR-33 impaired fibroblast proliferation in vitro, and ameliorated cardiac fibrosis induced by pressure overload in vivo.

Abstract P153: Role of Nonreceptor Tyrosine Kinases in Cardiac Fibrosis in a Mouse Model of Pressure Overload Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sundaravadivel Balasubramanian ◽  
Harinath Kasiganesan ◽  
Lakeya Quinones ◽  
Yuhua Zhang ◽  
Amy Bradshaw ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Pressure Overload ◽  
In Vivo Studies ◽  
Survival Pathways ◽  
And Function ◽  
Nonreceptor Tyrosine Kinases

During prolonged hypertrophic insult to the myocardium, while the function of cardiomyocytes needs to be protected, the hyperactivation of cardiac fibroblasts has to be curbed to prevent fibrosis. Previously, we showed that integrin-mediated non-receptor tyrosine kinase (NRTK) activation is required for normal functioning of both cardiac fibroblasts and cardiomyocytes. We hypothesized that inhibition of NRTKs in cardiac fibroblasts without affecting cardiomyocytes would be beneficial to the stressed myocardium. Our initial studies using kinase inactive forms of Src, Pyk2 and FAK expressed adenovirally in isolated primary cardiac fibroblasts showed that the pro-fibrotic signaling events as studied by fibronectin and collagen deposition are downregulated. Our in vivo studies in mouse transverse aortic constriction (TAC) model suggest that dasatinib, a multikinase NRTK inhibitor administration via a peritoneally implanted mini-osmotic pump is able to preserve ventricular geometry and function and reduce the accumulation of fibrotic extracellular matrix (ECM) proteins upon 4 wk pressure overload. Data obtained from cell culture experiments with kinase inactive NRTKs and dasatinib suggest that NRTK inhibition is able to reduce the proliferation, migration and mitogenic signaling in cardiac fibroblasts without affecting the cell survival pathways in cardiomyocytes. These data indicate that NRTKs play a significant pro-fibrotic role in cardiac fibroblasts and curbing the activity of NRTKs could be a potential therapeutic approach to treat fibrosis in hypertrophic heart diseases.

Novel role for cardiac myocyte-derived β-2 microglobulin in mediating cardiac fibrosis

2018 ◽  
Vol 132 (19) ◽  
pp. 2117-2120
Author(s):  
Michael J. Boyer ◽  
Satoru Eguchi
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Cardiac Fibroblasts ◽  
Significant Risk ◽  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Significant Risk Factor ◽  
Cardiac Complications

Hypertension is a significant risk factor for the development of cardiovascular ailments, including ischemic heart disease and diastolic dysfunction. In a recent issue of Clinical Science, Li et al. [Clin. Sci. (2018) 132, 1855–1874] report that β-2 microglobulin (β2M) is a novel secreted soluble factor released by cardiac myocytes during pressure overload that promotes profibrotic gene expression in cardiac fibroblasts both in vitro and in vivo. Their study further identifies elevated β2M levels as a possible biomarker for hypertensive patients with cardiac complications. The authors propose a mechanism that mechanically stretched cardiomyocytes release soluble β2M which, through paracrine communication with cardiac fibroblasts, transactivates epidermal growth factor receptor (EGFR) to initiate acute signal transduction and up-regulate profibrotic genes, thereby promoting fibrosis. Here, we will discuss the background, significance of the study, alternative mechanisms, and future directions.

scholarly journals Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice

2018 ◽  
Vol 46 (6) ◽  
pp. 2551-2560 ◽  
Author(s):  
LiJun Qian ◽  
Jian Hong ◽  
YanMei Zhang ◽  
MengLin Zhu ◽  
XinChun Wang ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Group A ◽  
Ischemic Diseases ◽  
Fibrotic Diseases ◽  
Signaling Activation

Background/Aims: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. Methods: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson’s trichrome staining to explore the function of S100A4. Results: We found significant increases of S100A4 level and cardiac fibrosis markers, and β-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and β-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited β-catenin signal pathway. Conclusion: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Planar Cell Polarity ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Cultured Fibroblasts

AbstractBackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation.Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage.ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

2018 ◽  
Vol 45 (5) ◽  
pp. 1955-1965 ◽  
Author(s):  
Xuelian Li ◽  
GuoYuan Wang ◽  
MuGe QiLi ◽  
HaiHai Liang ◽  
TianShi Li ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Pressure Overload ◽  
Collagen I ◽  
Signalling Pathways ◽  
Collagen Iii ◽  
The Impact

Background/Aims: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload–induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. Methods: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg-1·day-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Results: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Conclusions: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways.

scholarly journals Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts

2007 ◽  
Vol 102 (5) ◽  
pp. 2024-2032 ◽  
Author(s):  
Deepa H. Kumbar ◽  
Andrew VanBergen ◽  
Catherina Ocampo ◽  
Sunthorn Muangmingsuk ◽  
Andrew J. Griffin ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Volume Overload ◽  
Ang Ii ◽  
In Vivo Models ◽  
Erk Activation ◽  
Collagen Mrna ◽  
Collagen Expression

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, β-integrin-, PKC-, and transforming growth factor-β-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg·kg−1·day−1) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.

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