Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and phytoestrogens

Gardner, Jason D.; Brower, Gregory L.; Voloshenyuk, Tetyana G; Janicki, Joseph S.

doi:10.1152/ajpheart.00281.2007

Cited by 38 publications

(59 citation statements)

References 53 publications

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“…Female TG mice show no changes when compared with female or male NTG hearts. Differences in the development of cardiac hypertrophy between sexes have been previously noted (20,32). Thus, the increase in cardiomyocyte area and left ventricular hypertrophy with no change in heart weight to body weight ratio or female cardiac enlargement demonstrates the moderate nature of this hypertrophic phenotype.…”

Section: Resultsmentioning

confidence: 69%

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

Schulz

Correll

Sheikh

et al. 2012

Journal of Biological Chemistry

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Background: Changes in phosphorylation status of sarcomeric proteins allows rapid alteration of cardiac function. Results: Tropomyosin dephosphorylation results in myocyte hypertrophy with increases in SERCA2a (sarcoplasmic reticulum Ca 2ϩ ATPase 2a) expression and phospholamban phosphorylation but without functional changes. Conclusion: Tropomyosin phosphorylation can influence calcium regulatory proteins and cardiac remodeling in response to stress. Significance: This is the first report detailing that altering tropomyosin phosphorylation affects calcium handling proteins.

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Section: Resultsmentioning

confidence: 69%

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

Schulz

Correll

Sheikh

et al. 2012

Journal of Biological Chemistry

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“…Pellets were implanted subcutaneously between the shoulder blades 2 wk prior to fistula surgery. We have previously found that a dose of 0.02 mg/kg per day produces serum levels of ϳ35 pg/ml, which was comparable to the average estrogen level in intact female rats with functional ovaries (18).…”

Section: Surgical Proceduresmentioning

confidence: 61%

“…In contrast, female rats subjected to chronic volume overload develop an essentially concentric hypertrophy without the adverse features of myocardial remodeling seen in males, affording them cardioprotection from the subsequent development of heart failure (16 -19). This cardioprotection is lost in ovariectomized rats but can be largely restored by supplementary estrogen (8,16,18). Likewise, the adverse remodeling in male rats can be significantly attenuated by estrogen supplementation (19).…”

Section: Discussionmentioning

confidence: 99%

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

McLarty

Meléndez

Levick

et al. 2012

Physiological Genomics

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Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-␣ in male hearts secondary to sustained volume overload. These elevated levels of TNF-␣ are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n ϭ 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula ϩ Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (Ն2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-␣, which was downregulated by estrogen, and the TNF-␣ receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the ␤1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes. aortocaval fistula; tumor necrosis factor-␣; tumor necrosis factor-␣ receptors; prostaglandin; ␤1-integrin THE ABDOMINAL AORTOCAVAL FISTULA model of volume overload is an excellent approach in which to study sex differences in heart failure. In this model, males undergo collagen degradation and develop significant left ventricular (LV) wall thinning, ventricular dilatation, and increased myocardial compliance (5,9,10

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“…This apparent cardioprotection is lost following ovariectomy (6). Estrogen replacement delays the development of left ventricular (LV) hypertrophy and dilation, and it prevents the onset of congestive heart failure (CHF) in ovariectomized rats with volume overload (13). However, the mechanisms of estrogen's protective effects in prevention of adverse myocardial remodeling remain unclear.…”

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confidence: 99%

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Voloshenyuk

Gardner

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Our previous studies demonstrate that 17␤-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor ␣ and ␤ expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-␣ (ER␣), and ER␤, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ER␣ expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ER␤ expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats. extracellular matrix remodeling; ovariectomy; gender; hypertrophy; hormone; collagen; MT1-MMP; ventricle THE RISKS AND BENEFITS ASSOCIATED with estrogen replacement therapy remain uncertain. Conflicting results regarding the effect of estrogen replacement on the outcome of cardiovascular disease have been obtained from population studies, animal models, and clinical trials (2,16,20,21,32,33,61). The inconsistency of these findings demonstrates the lack of understanding of the mechanisms by which estrogen exerts its beneficial effects on the cardiovascular system. Using a rodent model, we demonstrated that hearts of intact female rats are resistant to chronic volume overload-induced adverse cardiac remodeling and dysfunction (12). This apparent cardioprotection is lost following ovariectomy (6). Estrogen replacement delays the development of left ventricular (LV) hypertrophy and dilation, and it prevents the onset of congestive heart failure (CHF) in ovariectomized rats with volume overload (13). However, the mechanisms of estrogen's protective effects in prevention of adverse myocardial remodeling remain unclear.Changes in extra...

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Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and phytoestrogens

Cited by 38 publications

References 53 publications

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

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

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

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