Involvement of Marinobufagenin in a Rat Model of Human Preeclampsia

Vu, Hop V.; Ianosi-Irimie, Monica; Pridjian, C; Whitbred, Joy; Durst, J; Bagrov, Alexei Y.; Федорова, О. В.; Pridjian, Gabriella; Puschett, Jules B.

doi:10.1159/000088461

Cited by 77 publications

(75 citation statements)

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“…Specific antibodies against MBG prevent both the acute and sustained NaCl-induced increase in arterial pressure (10). A prohypertensive effect of SPI in response to salt loading in hypertensive prone rats has been repeatedly observed (9,10,12,13,29). Our results show that a subacute increase in dietary NaCl elicits a sustained increase in MBG that is directly related to an increase in renal FENa and inversely related to NaCl sensitivity of SBP in population of normotensive middle-age and older women.…”

Section: Discussionsupporting

confidence: 56%

Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

Anderson¹,

Федорова²,

Morrell³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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AY, Lakatta EG. Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. Am J Physiol Regul Integr Comp Physiol 294: R1248-R1254, 2008. First published February 20, 2008 doi:10.1152/ajpregu.00782.2007.-Factors that mediate increases in salt sensitivity of blood pressure with age remain to be clarified. The present study investigated 1) the effects of high-NaCl intake on two Na pump inhibitors, endogenous ouabain (EO) and marinobufagenin (MBG), in middle-aged and older normotensive Caucasian women; and 2) whether individual differences in EO and MBG are linked to variations in sodium excretion or salt sensitivity. A change from 6 days of a lower (0.7 mmol ⅐ kg Ϫ1 ⅐ day Ϫ1 )-to 6 days of a higher (4 mmol ⅐ kg Ϫ1 ⅐ day Ϫ1 )-NaCl diet elicited a sustained increase in MBG excretion that directly correlated with an increase in the fractional Na excretion and was inversely related to age and to an age-dependent increase in salt sensitivity. In contrast, EO excretion increased only transiently in response to NaCl loading and did not vary with age or correlate with fractional Na excretion or salt sensitivity. A positive correlation of both plasma and urine levels of EO and MBG during salt loading may indicate a casual link between two Na pump inhibitors in response to NaCl loading, as observed in animal models. A linear mixed-effects model demonstrated that age, dietary NaCl, renal MBG excretion, and body mass index were each independently associated with systolic blood pressure. Thus, a sustained increase in MBG in response to acutely elevated dietary NaCl is inversely linked to salt sensitivity in normotensive middle-aged and older women, and a relative failure of MBG elaboration by these older persons may be involved in the increased salt sensitivity with advancing age. marinobufagenin; ouabain; hypertension NUMEROUS STUDIES HAVE REPORTED that the magnitude of the systolic blood pressure (SBP) response to acute changes in dietary NaCl intake, i.e., salt sensitivity of blood pressure, increases with advancing age (16,20,27,(32)(33)(34)(35). Specific determinants of the greater blood pressure response of older persons to dietary NaCl, however, remain to be identified.NaCl ingestion results in an increase in plasma volume and natriuresis. It has been postulated for some time that endogenous substances [sodium pump inhibitors (SPI)] are stimulated by increased Na intake and increase natriuresis by inhibiting renal tubular Na pumps to prevent renal reabsorption of filtered Na (6,18,30). However, such substances were not purified adequately in early studies, and their assays were nonspecific (17).More recently, SPI assays have improved and become more specific (3,14), and studies in various animal models and in humans have documented an increased elaboration of SPI in response to NaCl loading. This research has focused largely on two SPI: an endogenous ouabain (EO) and a bufadienoide, marinobufagenin (MBG). Differences in the kinetics and tissue actions of thes...

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Section: Discussionsupporting

confidence: 56%

Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

Anderson¹,

Федорова²,

Morrell³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In an animal model of preeclampsia, we have shown that urinary excretion of MBG is elevated prior to the development of hypertension indicating that it may play a key role in the pathogenesis of preeclampsia (7). In addition, administration of an anti-MBG antibody corrected the deoxycorticosterone acetate-salt hypertension in pregnant rats, which demonstrated elevated urinary excretion of MBG (7,8). These findings suggest that MBG might affect first trimester CTB function.…”

Section: Marinobufagenin (Mbg)mentioning

confidence: 73%

“…Preeclampsia is associated with shallow placentation, inadequate invasion, and insufficient remodeling of the maternal arteries (13,15). In an animal model of preeclampsia, we have shown that urinary excretion of MBG is elevated prior to the development of hypertension indicating that it may play a key role in the pathogenesis of preeclampsia (7). In addition, administration of an anti-MBG antibody corrected the deoxycorticosterone acetate-salt hypertension in pregnant rats, which demonstrated elevated urinary excretion of MBG (7,8).…”

Section: Marinobufagenin (Mbg)mentioning

confidence: 88%

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Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function

Uddin

Horvat

Glaser

et al. 2008

Journal of Biological Chemistry

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Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in the inhibition of Na؉ /K ؉ -ATPase. Increased plasma levels have been reported in patients with volume expansion-related hypertension. We have recently demonstrated that MBG impairs first trimester cytotrophoblast (CTB) cell proliferation, migration, and invasion, which may play a role in the development of preeclampsia. However, whether apoptosis contributes to altered CTB cell function by MBG remains unknown. Using the human extravillous CTB cell line SGHPL-4, we examined the effect of MBG and a similar Na ؉ /K ؉ -ATPase inhibitor, ouabain, on the phosphorylation status of Jnk, p38, and Src. Additionally, we measured apoptosis by caspase 9 and 3/7 activity and by annexin-V staining. We also investigated interleukin-6 (IL-6) secretion with or without p38 and Jnk inhibition. MBG significantly increased the phosphorylation of Jnk, p38, and Src and increased the expression of caspase 9 and 3/7 indicating the activation of apoptosis. MBG treatment also stimulated the expression of the early apoptosis marker, annexin-V, which was prevented by Jnk and p38 inhibition. MBG also stimulated the secretion of IL-6, which was attenuated by p38 inhibition. Ouabain had similar effects to those of MBG, suggesting that the apoptotic effects on CTB cells may be mediated by inhibition of Na ؉ /K ؉ -ATPase. In conclusion, the MBG-induced impairment of CTB function occurs via activation of Jnk, p38, and Src leading to increased apoptosis and IL-6 secretion. These observations may have clinical applicability with respect to the therapy of preeclampsia.

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“…149 In pregnant rats rendered hypertensive by deoxycorticosterone acetate and salt supplementation, uterine arteries exhibited enhanced sensitivity to the vasoconstrictor action of marinobufagenin, and an antimarinobufagenin antibody had an antihypertensive effect. 150 Thus, it appears that increases in circulating marinobufagenin levels are responsible for the Na + /K + -ATPase inhibition induced by preeclampsia and contribute to the pathogenesis of pre-eclampsia. Accordingly, low concentrations of marinobufagenin impair the differentiation of the cytotrophoblast in vitro.…”

Section: Role Of Cardiotonic Steroids In Pre-eclampsiamentioning

confidence: 99%

Endogenous digitalis: pathophysiologic roles and therapeutic applications

2008

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SUMMARYEndogenous digitalis-like factors, also called cardiotonic steroids, have been thought for nearly half a century to have important roles in health and disease. The endogenous cardiotonic steroids ouabain and marinobufagenin have been identified in humans, and an effector mechanism has been delineated by which these hormones signal through the sodium/potassium-transporting ATPase. These findings have increased interest in this field substantially. Although cardiotonic steroids were first considered important in the regulation of renal sodium transport and arterial pressure, subsequent work has implicated these hormones in the control of cell growth, apoptosis and fibrosis, among other processes. This Review focuses on the role of endogenous cardiotonic steroids in the pathophysiology of essential hypertension, congestive heart failure, end-stage renal disease and pre-eclampsia. We also discuss potential therapeutic strategies that have emerged as a result of the increased understanding of the regulation and actions of cardiotonic steroids.

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Involvement of Marinobufagenin in a Rat Model of Human Preeclampsia

Cited by 77 publications

References 59 publications

Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives

Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function

Endogenous digitalis: pathophysiologic roles and therapeutic applications

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