Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion

Booth, Erin A.; Lucchesi, Benedict R.

doi:10.1152/ajpheart.00993.2006

Cited by 21 publications

(16 citation statements)

References 46 publications

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“…In addition to the increasing number of incidents with oxidative damage and inflammatory processes, enhanced programmed cell death in IBH was also exhibited in the literature [9][10][11] . Programmed cell death is defined as apoptosis.…”

Section: Discussionmentioning

confidence: 91%

“…The sections were examined for the presence of edema, necrosis, inflammatory infiltration, apoptosis, vascular congestion and thrombosis and severity and prevalence of partial separation in apical epithelial cells. The histopathologist was blinded for group allocation and performed all analyses and graded microscopic changes in the colonic mucosa from 0 to 3 9,10 .…”

Section: Macroscopic Scoringmentioning

confidence: 99%

“…By these mechanisms, progesterone could prevent cellular apoptosis also in brain and heart tissues [5][6][7][8][9] . Building on these findings we performed a study aimed at evaluating the protective effect of treatment with progesterone in the TNBS-induced colitis rat model.…”

Section: Introductionmentioning

confidence: 99%

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The effect of progesterone in the prevention of the chemically induced experimental colitis in rats

Karatepe¹,

Altıok²,

Battal³

et al. 2012

Acta Cir. Bras.

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PURPOSE:To study the effects of progesterone on an experimental colitis model. METHODS:Wistar albino rats were treated subcutaneously with 2mg/kg once a day during seven days Colitis was induced by intrarectal administration of 5mg trinitrobenzene sulfonic acid (TNBS). Disease activities, macroscopic and microscopic scores were evaluated.To determine the response provoked by progesterone we measured Colonic malondialdehyde (MDA), TNF alfa, IL-6 and Nitric oxide (NO) levels in addition to the MPO (Myeloperoxidase) and caspase-3 activities. RESULTS:Progesterone ameliorated significantly the macroscopic and microscopic scores. TNBS-induced colitis significantly increased the colonic MDA levels and caspase-3 activities in group 2 in comparison to the control group. The results of the study revealed a decline in MDA, NO, IL6 and TNF-α levels in the colon tissue and in blood due to progesterone therapy in group 3 when compared to the group 2, a significant improvement. Progesterone treatment was associated with decreased MDA, MPO, TNF alfa and caspase-3 activity. CONCLUSION:Progesterone therapy decreased oxidative damage in the colonic mucosa.Key words: Progesterone. Colitis. Inflammation. Colon. Rats. RESUMO OBJETIVO:Investigar os efeitos da progesterona em um modelo de colite experimental. MÉTODOS:Ratos albinos Wistar foram tratados subcutaneamente com 2mg/kg por dia durante sete dias. A colite foi induzida por administração intrarretal de 5mg ácido sulfônico trinitrobenzeno (TNBS). Foram avaliadas as atividades da doença, escores macroscópicos e microscópicos Para determinar a resposta provocada pela progesterona foi medida no cólon os níveis de malondialdeído (MDA), TNF alfa, IL-6 e óxido nítrico (NO), além da atividade da MPO (Myeloperoxidase) e caspase-3. RESULTADOS:A progesterone melhorou significantemente os escores macroscópicos e microscópicos. A colite induzida pelo TNBS significantemente aumentou os níveis colônicos de MDA e a atividade da caspase-3 no grupo 2 em comparação com o grupo controle.Os resultados do estudo revelaram um declínio nos níveis de MDA, NO, IL6 e TNF-α no tecido colônico e no sangue devido à terapia com a progesterona no grupo 3 quando comparado ao grupo 2. O tratamento com a progesterona foi associado com decréscimo do MDA, MPO, TNF alfa e atividade da caspase-3. CONCLUSÃO:A terapia com progesterona decresce o dano oxidativo na mucosa do cólon.Descritores: Progesterona. Colite. Inflamação. Colo. Ratos.Karatepe O et al.

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Section: Discussionmentioning

confidence: 91%

Section: Macroscopic Scoringmentioning

confidence: 99%

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The effect of progesterone in the prevention of the chemically induced experimental colitis in rats

Karatepe¹,

Altıok²,

Battal³

et al. 2012

Acta Cir. Bras.

View full text Add to dashboard Cite

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“…Infarct size is of pivotal importance for the extent of cardiac remodeling and chronic HF following MI. Booth and Lucchesi (2007) and Jeanes et al (2006) previously reported that an acute addition of MPA to an E2 treatment resulted in an extension of the necrotic zone after a cardiac ischemic effect. Nonetheless, those findings were limited to the events occurring during the first 4 hours after reperfusion injury.…”

Section: Discussionmentioning

confidence: 98%

Medroxyprogesterone Acetate Aggravates Oxidative Stress and Left Ventricular Dysfunction in Rats with Chronic Myocardial Infarction

Arias-Loza

Frantz

et al. 2011

Toxicol Pathol

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The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17b-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.

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“…For example, MPA attenuates the beneficial effects of estrogens on endothelial-dependent relaxation and release of NO (antimitogenic molecule), 10,17,18 increases vascular procoagulant activity by upregulating thrombin receptor PAR-1 expression, 15 abrogates the cardioprotective and anti-inflammatory effects of estradiol, 19 attenuates the favorable effects of orally administered estrogens on high-density lipoprotein, 9 and abrogates the inhibitory effects of estradiol on injury-induced neointima formation. 12 Finally, although the above findings suggest that MPA can abrogate the protective effects of estradiol, it should be noted that the estrogen alone arm of the Women's Health Initiative Study did not show positive results, suggesting that factors other than MPA may also contribute to the lack of cardiovascular protective actions by estrogens in the Women's Health Initiative Study.…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Abrogates the Inhibitory Effects of Estradiol on Vascular Smooth Muscle Cells by Preventing Estradiol Metabolism

et al. 2008

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Abstract-Sequential conversion of estradiol (E) to 2/4-hydroxyestradiols and 2-/4-methoxyestradiols (MEs) by CYP450s and catechol-O-methyltransferase, respectively, contributes to the inhibitory effects of E on smooth muscle cells (SMCs) via estrogen receptor-independent mechanisms. Because medroxyprogesterone (MPA) is a substrate for CYP450s, we hypothesized that MPA may abrogate the inhibitory effects of E by competing for CYP450s and inhibiting the formation of 2/4-hydroxyestradiols and MEs. To test this hypothesis, we investigated the effects of E on SMC number, DNA and collagen synthesis, and migration in the presence and absence of MPA. The inhibitory effects of E on cell number, DNA synthesis, collagen synthesis, and SMC migration were significantly abrogated by MPA. For example, E (0.1mol/L) reduced cell number to 51Ϯ3.6% of control, and this inhibitory effect was attenuated to 87.5Ϯ2.9% by MPA (10 nmol/L). Treatment with MPA alone did not alter any SMC parameters, and the abrogatory effects of MPA were not blocked by RU486 (progesterone-receptor antagonist), nor did treatment of SMCs with MPA influence the expression of estrogen receptor-␣ or estrogen receptor-␤. In SMCs and microsomal preparations, MPA inhibited the sequential conversion of E to 2-2/4-hydroxyestradiol and 2-ME. Moreover, as compared with microsomes treated with E alone, 2-ME formation was inhibited when SMCs were incubated with microsomal extracts incubated with E plus MPA. Our findings suggest that the inhibitory actions of MPA on the metabolism of E to 2/4-hydroxyestradiols and MEs may negate the cardiovascular protective actions of estradiol in postmenopausal women receiving estradiol therapy combined with administration of MPA. Key Words: estradiol Ⅲ progestins Ⅲ cytochrome P450 Ⅲ metabolism Ⅲ cardiovascular disease Ⅲ vascular remodeling S tudies using pharmacological agents to block or induce the conversion of estradiol to hydroxyestradiols (mediated by CYP450s) and to methoxyestradiols (mediated by catechol-O-methyltransferase acting on hydroxyestradiols) and studies in knockout mice that cannot form methoxyestradiols provide strong evidence that methoxyestradiols mediate the inhibitory effects of estradiol on smooth muscle cell (SMC) DNA and collagen synthesis, as well as SMC proliferation and migration. 1-3 Also, evidence supports the conclusion that methoxyestradiols mediate the inhibitory effects of estradiol on injuryinduced neointima formation, 4 as well as the inhibitory effects of estradiol on cardiac fibroblasts 5 and glomerular mesangial cells, 5 which are relevant for the cardiovascular system. Medroxyprogesterone (MPA) is a synthetic progestin often given concomitantly with estrogens during hormone replacement therapy. However, because MPA is a substrate for CYP450s and is hydroxylated, it is feasible that MPA competes with estradiol for CYP450s and inhibits metabolism of estradiol to hydroxyestradiols and consequently to inhibitory methoxyestradiols.Several observations support this hypothesis: (1) increased adverse ...

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Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion

Abstract: Booth EA, Lucchesi BR. Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17␤-estradiol in an in vivo model of myocardial ischemia and reperfusion.

Cited by 21 publications

References 46 publications

The effect of progesterone in the prevention of the chemically induced experimental colitis in rats

The effect of progesterone in the prevention of the chemically induced experimental colitis in rats

Medroxyprogesterone Acetate Aggravates Oxidative Stress and Left Ventricular Dysfunction in Rats with Chronic Myocardial Infarction

Medroxyprogesterone Abrogates the Inhibitory Effects of Estradiol on Vascular Smooth Muscle Cells by Preventing Estradiol Metabolism

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