Estrogenic modulation of inflammation-related genes in male rats following volume overload

McLarty, Jennifer L.; Meléndez, Giselle C.; Levick, Scott P.; Bennett, Shanté; Sabo‐Attwood, Tara; Brower, Gregory L.; Janicki, Joseph S.

doi:10.1152/physiolgenomics.00146.2011

Cited by 5 publications

(10 citation statements)

References 42 publications

(61 reference statements)

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“…Cardiac MCs play a pivotal role in adverse remodeling which is countered by estrogen’s ability to induce protective, phenotypic MC changes 9–11,25 . Given that myocardial chymase is primarily produced and localized in cardiac MCs and that decreased myocardial fibrosis was reported following a reduction in chymase activity in hypertensive rats 22 , we hypothesized that estrogen prevents adverse myocardial remodeling secondary to a sustained cardiac pressure overload via its ability to either diminish the MC synthesis of chymase and/or MC degranulation.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Jubair

Janicki

2015

Hypertension

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Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized rats. Three days prior to creating the constriction, additional groups of ovariectomized rats began receiving 17β-Estradiol, a chymase inhibitor, or a mast cell stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, mast cell density and degranulation, and myocardial and plasma chymase levels were assessed 18 days post-surgery. Aortic constriction resulted in ventricular hypertrophy in intact and ovariectomized groups while collagen volume fraction was increased only in ovariectomized rats. Chymase protein content was increased by aortic constriction in the intact and ovariectomized groups with the magnitude of the increase being greater in ovariectomized rats. Mast cell density and degranulation, plasma chymase levels and myocardial active transforming growth factor- 1 levels were increased by aortic constriction only in ovariectomized rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, mast cell density and degranulation, plasma chymase and myocardial active transforming growth factor- 1 as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction induced ventricular hypertrophy and collagen volume fraction in the ovariectomized rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects except for the reduction of chymase content. We conclude that the estrogen-inhibited release of mast cell chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Jubair

Janicki

2015

Hypertension

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“…However, whether estrogen confers cardioprotection by modulating the influence of inflammatory cells is unknown. As a follow-up study to those reporting that estrogen provides cardioprotection in female and male rats in a model of chronic volume overload, we performed a polymerase chain reaction array analysis on hearts from untreated and estrogen-treated male rats exposed to chronic cardiac volume overload 5. This array analysis identified several inflammation-related genes, including the genes for TNF-α, that were regulated by estrogen, raising the possibility that estrogen may modulate inflammatory cell function in the diseased heart.…”

Section: Discussionmentioning

confidence: 99%

“…However, estrogen is known to modulate inflammatory cells at the transcriptional level since estrogen receptors are nuclear hormone transcription factors that subsequently bind estrogen response elements to activate or suppress specific gene targets 45. We have recently shown in a model of chronic cardiac volume overload that estrogen downregulated gene transcription of TNF-α,5 thus preventing the increased levels of TNF-α that are normally seen in the heart in response to volume overload 3,5. Since TNF-α causes MMP activation and collagen degradation in the volume-overloaded heart,46,47 actions consistent with what we observed in our inflammatory cell-fibroblast Boyden chamber study, we sought to determine if TNF-α mediated the effects of inflammatory cells on cardiac fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen supplementation in ovariectomized female rats restores cardioprotection2 and also confers cardioprotection in male rats 4. Using a polymerase chain reaction array screening approach, we recently found the expression of several inflammatory genes to be regulated by estrogen in male hearts exposed to volume overload 5. This raises the possibility that the cardioprotection provided by estrogen may, in part, be due to modulation of inflammatory cells by estrogen.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen modulates the influence of cardiac inflammatory cells on function of cardiac fibroblasts

McLarty¹,

Li²,

Levick³

et al. 2013

JIR

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BackgroundInflammatory cells play a major role in the pathology of heart failure by stimulating cardiac fibroblasts to regulate the extracellular matrix in an adverse way. In view of the fact that inflammatory cells have estrogen receptors, we hypothesized that estrogen provides cardioprotection by decreasing the ability of cardiac inflammatory cells to influence fibroblast function.MethodsMale rats were assigned to either an untreated or estrogen-treated group. In the treated group, estrogen was delivered for 2 weeks via a subcutaneous implanted pellet containing 17β-estradiol. A mixed population of cardiac inflammatory cells, including T-lymphocytes (about 70%), macrophages (about 12%), and mast cells (about 12%), was isolated from each rat and cultured in a Boyden chamber with cardiac fibroblasts from untreated adult male rats for 24 hours. To examine if tumor necrosis factor-alpha (TNF-α) produced by inflammatory cells represents a mechanism contributing to the stimulatory effects of inflammatory cells on cardiac fibroblasts, inflammatory cells from the untreated group were incubated with cardiac fibroblasts in a Boyden chamber system for 24 hours in the presence of a TNF-α-neutralizing antibody. Cardiac fibroblasts were also incubated with 5 ng/mL of TNF-α for 24 hours. Fibro-blast proliferation, collagen synthesis, matrix metalloproteinase activity, β1 integrin protein levels, and the ability of fibroblasts to contract collagen gels were determined in all groups and statistically compared via one-way analysis of variance.ResultsInflammatory cells from the untreated group resulted in: 1) an increased fibroblast proliferation, collagen production and matrix metalloproteinase activity; and 2) a loss of β1 integrin protein and a reduced ability to contract collagen gels. In contrast, inflammatory cells from the treated group resulted in: 1) an attenuated fibroblast proliferation; 2) a nonsignificant reduction in collagen production; 3) the prevention of matrix metalloproteinase activation and the loss of β1 integrin by fibroblasts and 4) a preservation of the fibroblasts’ ability to contract collagen gels. The TNF-α neutralizing antibody attenuated or prevented the untreated inflammatory cell-induced fibroblast proliferation, collagen production, matrix metalloproteinase activation and loss of β1 integrin protein as well as preserved fibroblast contractile ability. Incubation with TNF-α yielded changes in the cardiac fibroblast parameters that were directionally similar to the results obtained with untreated inflammatory cells.ConclusionThese results and those of our previous in vivo studies suggest that a major mechanism by which estrogen provides cardioprotection is its ability to modulate synthesis of TNF-α by inflammatory cells, thereby preventing inflammatory cell induction of cardiac fibroblast events that contribute to adverse extracellular matrix remodeling.

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“…The rat with aorto‐caval fistula (ACF) presents a well‐defined model of CHF due to volume overload, characterized by activation of the circulating and intrarenal RAS, cardiac remodeling and signs of failure including congestion; in many respects the model imitates the course of CHF in untreated humans . Despite such suitable features, the model was employed in but few studies which focused mostly on the sex‐based differences in the pattern of global myocardial remodelling, mainly those observed during the compensation phase of CHF …”

Section: Introductionmentioning

confidence: 99%

Sex‐linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats with volume overload induced using aorto‐caval fistula

Červenka

Škaroupková

Kompanowska-Jezierska

et al. 2016

Clin Exp Pharma Physio

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The role of hypertension and the renin-angiotensin system (RAS) in sex-related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren-2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto-caval fistula (ACF). The primary aim of the study was to examine long-term CKD- and CHF-related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex-related differences. The follow-up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX-induced CKD. Second, in contrast, TGR exhibited important sex-related differences in the course of ACF-induced CHF-related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX-induced CKD and ACF-induced CHF-related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX-induced CKD and ACF-induced CHF was significantly worsened as compared with rat groups that were exposed to 'single organ disease'. Collectively, our present results clearly show that CKD aggravates long-term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD- and CHF-related mortality, especially in animals with combined CKD and CHF.

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Estrogenic modulation of inflammation-related genes in male rats following volume overload

Cited by 5 publications

References 42 publications

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Estrogen modulates the influence of cardiac inflammatory cells on function of cardiac fibroblasts

Sex‐linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats with volume overload induced using aorto‐caval fistula

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