Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation

Pechenino, Angela S.; Lin, Li; Mbai, Fiona N.; Lee, Alison R.; He, Xian Min; Stallone, John N.; Knowlton, Anne A

doi:10.1152/physiolgenomics.00228.2010

Cited by 37 publications

(28 citation statements)

References 53 publications

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“…While estrogen has been shown to decrease TNF-␣ gene expression in heart tissue (43), a direct genomic mechanism as a possible point for regulation of myocardial remodeling by estrogen has not been substantiated prior to the results herein. However, estrogen has been shown to decrease TNF-␣ in myocardial tissues without myocardial stress (35) and in the ischemic brain (39). This is also the first study linking estrogen to cardiac TNF-␣ receptor expression.…”

Section: Discussionmentioning

confidence: 72%

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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Section: Discussionmentioning

confidence: 72%

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

McLarty

Meléndez

Levick

et al. 2012

Physiological Genomics

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“…(55–57) Recently we have demonstrated that delayed estrogen replacement in aged ovariectomized (OVX) female Norway Brown(NB) rats led to a substantial number of gene changes in the heart including increased expression of CD11b, MIP-1β, STAT3, EMAP II, fibronectin, caspase 6 and MADD. (58) Although neither TNFα or iNOS had increased RNA levels in this model, both had marked increase in their protein levels with late replacement. A striking finding was increased expression of genes that stimulate leukocyte attraction and adhesion, initial steps in atherosclerosis.…”

Section: Introductionmentioning

confidence: 76%

“…Since TNFα enhances the expression of adhesion molecules this would only further promote atherosclerosis. (58)…”

Section: Introductionmentioning

confidence: 99%

Estrogen and the female heart

Knowlton

Korzick

2014

Molecular and Cellular Endocrinology

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Estrogen has a plethora of effects in the cardiovascular system. Studies of estrogen and the heart span human clinical trials and basic cell and molecular investigations. Greater understanding of cell and molecular responses to estrogens can provide further insights into the findings of clinical studies. Differences in expression and cellular/intracellular distribution of the two main receptors, estrogen receptor (ER) α and β, are thought to account for the specificity and differences in responses to estrogen. Much remains to be learned in this area, but cellular distribution within the cardiovascular system is becoming clearer. Identification of GPER as a third ER has introduced further complexity to the system. 17β-estradiol (E2), the most potent human estrogen, clearly has protective properties activating a signaling cascade leading to cellular protection and also influencing expression of the protective heat shock proteins (HSP). E2 protects the heart from ischemic injury in basic studies, but the picture is more involved in the whole organism and clinical studies. Here the complexity of E2's widespread effects comes into play and makes interpretation of findings more challenging. Estrogen loss occurs primarily with aging, but few studies have used aged models despite clear evidence of differences between the response to E2 deficiency in adult and aged animals. Thus more work is needed focusing on the effects of aging vs. estrogen loss on the cardiovascular system.

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“…It has been suggested that increased expression of inflammatory genes, such as TNF-α may be involved in some of deleterious effect of delayed E2 administration (Pechenino et al 2011). The alterations of estrogen-mediated inflammatory biomarkers in women has been reported to correlate with the timing of initiation of estrogen treatment, type of drug, and the gene polymorphisms of ER (Dubey et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Antioxidative effect of aspirin on vascular function of aged ovariectomized rats

Demirci

Demir

Dost

et al. 2013

AGE

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This study investigated the vascular effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in the very late stage of postmenopausal vascular aging and looked for a better choice of anti-inflammatory drug for women in reducing the cardiovascular risk by decreasing the oxidant status in this term. The rat aorta isolated from young and old rats that were treated with either aspirin (10 mg/kg/day) or indomethacin (INDO, 1 mg/kg/day) within last 10 weeks after 16-month overiectomy (OVX) follow-up. Endothelium-dependant acetylcholine (Ach, 0.001-30 μM) and independent sodium nitroprusside (SNP, 0.0001-3 μM) relaxant; α-receptor phenylephrine (PE, 0.001-30 μM) and voltage-dependant high potassium (KCl; 40 mM) contractile responses were assessed. Total oxidant and antioxidant status were measured from the serum samples. Aged OVX rat's both aortic endothelium and smooth muscle relaxation were significantly less than of younger ones, whereas their contractile functions tended to decrease. INDO did not treat the Ach, SNP responses, whereas it increased the PE and KCl contractility. Aspirin improved the relaxation function and antioxidant capacity and decreased the oxidant status. These data demonstrate that even if they are in the very late stage of life and menopause, the analgesic choices could restore the well established endothelial dysfunction, vascular stiffness, and oxidant status.

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Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation

Abstract: Pechenino AS, Lin L, Mbai FN, Lee AR, He XM, Stallone JN, Knowlton AA. Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation.

Cited by 37 publications

References 53 publications

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

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

Estrogen and the female heart

Antioxidative effect of aspirin on vascular function of aged ovariectomized rats

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