Estradiol-Treated Mesenchymal Stem Cells Improve Myocardial Recovery After Ischemia

Erwin, Graham S.; Crisostomo, Paul R.; Wang, Yue; Wang, Meijing; Markel, Troy A.; Guzman, Mike J.; Sando, Ian C.; Sharma, Rahul; Meldrum, Daniel R.

doi:10.1016/j.jss.2008.02.006

Cited by 53 publications

(37 citation statements)

References 37 publications

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“…8,32,36 Estrogen increases protein S-nitrosylation, a common posttranslational protein modification, 37 and reduces inflammatory markers 32,38 and afterload-or agonist-induced cardiac hypertrophy via the inhibition of calcineurin hypertrophic transcription factor and mitogen-activated protein kinase signaling pathways. 39 Estrogen also improves endothelial and myocardial function after ischemia by an antiapoptotic and pro-survival effect on cardiomyocytes, 40,41 endothelial progenitor cell mobilization 42 and mesenchymal stem cell-mediated vascular endothelial growth factor release. 43,44 These rapid effects of estrogen on the action of CF6 were not examined in this study.…”

Section: Discussionmentioning

confidence: 99%

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

et al. 2012

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In male coupling factor 6 (CF6)-overexpressing transgenic (TG) mice, a high-salt diet induces hypertension and cardiac systolic dysfunction with excessive reactive oxygen species generation. However, the role of gender in CF6-mediated pathophysiology is unknown. We investigated the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction and Rac1 activity, which activates radical generation and the mineralocorticoid receptor, in female TG mice. Fifteen-week-old male and female TG and wild-type (WT) mice were fed a normal-or high-salt diet for 60 weeks. Systolic and diastolic blood pressures were higher in the TG mice fed a high-salt diet than in those fed a normal-salt diet at 20-60 weeks in males but only at 60 weeks in females. The blood pressure elevation under high-salt diet conditions was concomitant with a decrease in left ventricular fractional shortening. In the WT mice, neither blood pressure nor cardiac systolic function was influenced by a high-salt diet. In the female TG mice, bilateral ovariectomy induced hypertension with cardiac systolic dysfunction 8 weeks after the initiation of a high-salt diet. The ratios of Rac1 bound to guanosine triphosphate (Rac1-GTP) to total Rac1 in the heart and kidneys were increased in the ovariectomized TG mice, and estrogen replacement abolished the CF6-mediated pathophysiology induced under the high-salt diet conditions. The overexpression of CF6 induced salt-sensitive hypertension, complicated by systolic cardiac dysfunction, but its onset was delayed in females. Estrogen has an important role in the regulation of CF6-mediated pathophysiology, presumably via the downregulation of Rac1. Hypertension Research (2012) 35, 539-546; doi:10.1038/hr.2011.232; published online 19 January 2012Keywords: coupling factor 6; estrogen; heart failure; hypertension; salt INTRODUCTION Premenopausal women have a lower risk and incidence of hypertension and cardiovascular disease than age-matched men. However, this gender advantage gradually disappears after menopause. Although blood pressure is lower in premenopausal women than in men, after menopause, it increases to levels similar to or higher than those of agematched men. 1,2 The recent Nurse's Health Study 3 and WISE Study, 4 as well as others, 5 have demonstrated that compared with women with normal endogenous estrogen levels, young women undergoing early menopause owing to ovarian dysfunction or bilateral ovariectomy have an increased risk of cardiovascular disease. In animal models of cardiovascular disease, females exhibited lower mortality, less vascular injury, better preservation of cardiovascular function, and slower progression to decompensated heart failure than did males, although such differences were abolished after ovariectomy or induction of a deficiency in endogenous estrogen. 6,7-9 These findings clearly suggest that sex hormones have a cardioprotective role in women. Although randomized, prospective, primary or secondary prevention trials failed

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Section: Discussionmentioning

confidence: 99%

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

et al. 2012

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“…Compared with male MSCs, vascular endothelial growth factor (VEGF) production was significantly higher and expression of proinflammatory cytokines, TNF-α and IL-6 significantly lower in female MSCs induced by lipopolysaccharide (LPS) and hypoxia [15,16]. Additionally, estrogen-treated MSCs provoke significantly higher VEGF production, and the hearts infused with estrogen-treated MSCs exhibited convincingly greater left ventricular developed pressure (LVDP) and improved contractility and compliance compared to the hearts with estrogen-untreated MSCs or vehicles, which suggests that estrogen may have indirect cardioprotective effects via enhancement of MSCs paracrine pathways [17]. It is well known that macrophages and cardiomyocytes release proinflammatory cytokines following injury.…”

Section: Effects Of Estrogen On Cardiac Repair After Ischemic Infarctionmentioning

confidence: 99%

Effects of estrogen on diverse stem cells and relevant intracellular mechanisms

Sun

Wang

Shiyu

2010

Sci. China Life Sci.

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Sexual dimorphism definitely exists in the pathogenesis of a variety of cardiovascular, neurodegenerative and bone metabolism disorders. Estrogen affects the healing of ischemic myocardium partially through paracrine growth hormone production by bone marrow mesenchymal stem cells (MSCs) and facilitation on mobilization of endothelial progenitors cells (EPCs) to the ischemic myocardium. Estrogen can also inhibit the proliferation of the cardiac fibroblasts. Therefore, estrogen effectively enhances the neovascularization at the ischemic border zone and limits pathological myocardial remodeling. Moreover, estrogen increases proliferation of embryonic neural stem cells and accelerates differentiation of neurons during neurogenesis, suggesting a possible role of estrogen in transplantation of neural stem cells as a therapeutic approach for neurodegenerative diseases. Finally, estrogen can modulate osteogenic progenitors and osteoclasts, preventing the osteoporosis. In general, estrogen offers significant benefits on diverse stem/progenitor cell populations. A great understanding of estrogens on these cells and relevant intracellular mechanisms will allow modulation of the potent stem cells directly for the ultimate clinical applications.

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“…However, there has been increasing concern over the low rate of engraftment of transplanted stem cells as a majority of them are lost within a few days of transplantation (2,31,39,43). To counter such loss upon transplantation, MSCs have been preconditioned in several ways, including hypoxic preconditioning (HPC), to enhance the retention and survival of these cells in the MI heart (12,16,18,41,42). In our earlier studies we observed that the ischemic region in the infarct heart of murine models could reach an oxygen level as low as 0.2% (4,25), which would imply that the survival and proliferation of transplanted stem cells in the infarct tissue would require the cells to adapt to very low oxygen tension in the infarct heart.…”

mentioning

confidence: 99%

Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells

Chacko

Ahmed

Selvendiran

et al. 2010

American Journal of Physiology-Cell Physiology

177

114

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preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells. Am J Physiol Cell Physiol 299: C1562-C1570, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00221.2010.-Stem cells transplanted to the ischemic myocardium usually encounter massive cell death within a few days of therapy. Hypoxic preconditioning (HPC) is currently employed as a strategy to prepare stem cells for increased survival and engraftment in the heart. However, HPC of stem cells has provided varying results, supposedly due to the differences in the oxygen concentration, duration of exposure, and passage conditions. In the present study, we determined the effect of HPC on rat mesenchymal stem cells (MSCs) exposed to 0.5% oxygen concentration for 24, 48, or 72 h. We evaluated the expression of prosurvival, proangiogenic, and functional markers such as hypoxia-inducible factor-1␣, VEGF, phosphorylated Akt, survivin, p21, cytochrome c, caspase-3, caspase-7, CXCR4, and c-Met. MSCs exposed to 24-h hypoxia showed reduced apoptosis on being subjected to severe hypoxic conditions. They also had significantly higher levels of prosurvival, proangiogenic, and prodifferentiation proteins when compared with longer exposure (72 h). Cells taken directly from the cryopreserved state did not respond effectively to the 24-h HPC as those that were cultured under normoxia before HPC. Cells cultured under normoxia before HPC showed decreased apoptosis, enhanced expression of connexin-43, cardiac myosin heavy chain, and CD31. The preconditioned cells were able to differentiate into the cardiovascular lineage. The results suggest that MSCs cultured under normoxia before 24-h HPC are in a state of optimal expression of prosurvival, proangiogenic, and functional proteins that may increase the survival and engraftment in the infarct heart. These results could provide further insights into optimal preparation of MSCs which would greatly influence the effectiveness of cell therapy in vivo. myocardial infarction; cell therapy THE OXYGEN CONCENTRATION in the microenvironment of stem cells plays an important role in controlling stem cell potency, proliferation, and differentiation ability (1,26,28). Stem cells that are normally cultured at ambient air in an in vitro environment differ in their exposure to the concentration of oxygen, compared with their natural physiological niches where they reside and function (7, 9). During cell transplantation procedures to treat conditions such as myocardial infarction (MI), the cultured stem cells encounter a sudden shortage in oxygen availability when transplanted into an ischemic heart tissue. A growing body of evidence attributes failure of stem cell therapy to the extensive loss of transplanted stem cells upon introducing them to such a harsh ischemic environment, which is high in inflammation factors and free radicals generated by oxidative stress (14, 38). Varying the oxygen exposure level while culturing the stem cells may play a major role in determining the survival of...

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Estradiol-Treated Mesenchymal Stem Cells Improve Myocardial Recovery After Ischemia

Abstract: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.

Cited by 53 publications

References 37 publications

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

Effects of estrogen on diverse stem cells and relevant intracellular mechanisms

Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells

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