Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

Федорова, О. В.; Емельянов, И. В.; Bagrov, K.A.; Grigorova, Yulia; Wei, Wen Bin; Juhász, Ondrej; Frolova, Elena Vladimirovna; Marshall, Christine; Lakatta, Edward G.; Конради, А. О.; Bagrov, Alexei Y.

doi:10.1097/hjh.0000000000000591

Cited by 33 publications

(68 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was shown that certain inhibitors of Na ϩ -K ϩ -ATPase increase collagen synthesis by cultured rat cardiac fibroblasts, human dermal fibroblasts, or rat vascular SM cells (13)(14)(15)(16). However, these studies have not rigorously examined the effect of these compounds on the expression of myofibroblast differentiation markers, on the magnitude of their effect relative to that of TGF-␤, or on their effect on TGF-␤-induced myofibroblast differentiation.…”

Section: B Cmentioning

confidence: 99%

Regulation of myofibroblast differentiation by cardiac glycosides

Reed

Кольцова

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

] ratio may promote the expression of cyclooxygenase-2 (COX-2), a critical enzyme in the synthesis of prostaglandins. Given antifibrotic effects of prostaglandins through activation of protein kinase A (PKA), we examined if cardiac glycosides stimulate COX-2 expression in human lung fibroblasts and how they affect myofibroblast differentiation. Ouabain stimulated a profound COX-2 expression and a sustained PKA activation, which was blocked by COX-2 inhibitor or by COX-2 knockdown. Ouabain-induced COX-2 expression and PKA activation were abolished by the inhibitor of the Na ϩ /Ca 2ϩ exchanger, KB-R4943. Ouabain inhibited transforming growth factor-␤ (TGF-␤)-induced Rho activation, stress fiber formation, serum response factor activation, and the expression of smooth muscle ␣-actin, collagen-1, and fibronectin. These effects were recapitulated by an increase in intracellular [Na ϩ ]/[K ϩ ] ratio through the treatment of cells with K ϩ -free medium or with digoxin. Although inhibition of COX-2 or of the Na ϩ /Ca 2ϩ exchanger blocked ouabain-induced PKA activation, this failed to reverse the inhibition of TGF-␤-induced Rho activation or myofibroblast differentiation by ouabain. Together, these data demonstrate that ouabain, through the increase in intracellular [Na ϩ ]/[K ϩ ] ratio, drives the induction of COX-2 expression and PKA activation, which is accompanied by a decreased Rho activation and myofibroblast differentiation in response to TGF-␤. However, COX-2 expression and PKA activation are not sufficient for inhibition of the fibrotic effects of TGF-␤ by ouabain, suggesting that additional mechanisms must exist. ouabain; digoxin; intracellular sodium-to-potassium ion ratio; cyclooxygenase-2 IDIOPATHIC PULMONARY FIBROSIS (IPF) is a progressive fatal disease characterized by parenchymal fibrosis and structural distortion of the lungs. Age-adjusted mortality due to pulmonary fibrosis is increasing, and it poses a vexing clinical challenge given the lack of efficacious therapy. IPF is thought to be a disorder of abnormal wound healing (54), in which the initial trigger to the fibrotic response is injury to the alveolar epithelial cell, followed by an exuberant nonresolving woundhealing response (50). Injury of alveolar epithelial cells is thought to result in the elaboration of a fibrinous provisional matrix and activation of several proinflammatory, procoagulant, and profibrotic mediators, of which transforming growth factor-␤1 (TGF-␤1) is the most established (47). Fibroblasts, under stimulation of TGF-␤1, respond by altering their gene expression profile with de novo expression of cytoskeletal and contractile proteins normally found within smooth muscle (SM) cells, modified focal adhesion complexes, and components of the extracellular matrix (18,27). These SM-like fibroblasts are called myofibroblasts and display a phenotype that is in an intermediate state between fibroblasts and SM cells (10,19). Several cytoskeletal and SM proteins are expressed in myofibroblasts, including SM ␣-actin, the most established m...

show abstract

Section: B Cmentioning

confidence: 99%

Regulation of myofibroblast differentiation by cardiac glycosides

Reed

Кольцова

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…There is extensive evidence implicating CS in the pathogenesis of various models of salt‐dependent hypertension and in the potential end‐organ sequelae associated with such elevation of BP . We initiated these studies to determine whether CS might be relevant to BP levels in the widely used SHR model of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Serum Marinobufagenin in the Spontaneously Hypertensive Rat and the Relationship to Blood Pressure

Dmitrieva

Cranford

Doris

2017

JAHA

View full text Add to dashboard Cite

BackgroundWe have investigated serum levels of immunoreactive marinobufagenin (MBG) in 16‐ to 20‐week‐old spontaneously hypertensive rats (SHRs)‐A3 and in the normotensive Wistar‐Kyoto (WKY) rat strain in the absence of salt loading, and we have investigated the genetic control of serum MBG.Methods and ResultsWe genotyped the F2 progeny of an SHR‐A3×WKY intercross using a genome‐wide panel of 253 single‐nucleotide polymorphism markers that were dimorphic between SHR‐A3 and WKY and measured serum MBG by ELISA. Serum MBG levels were lower in SHR‐A3 than WKY rats (0.39±0.07 and 1.27±0.40 nmol/L, respectively), suggesting that MBG may not play a role in the markedly divergent blood pressure measured by telemetry in rats of these 2 strains (SHR‐A3 and WKY, 198.3±4.43 and 116.8±1.51 mm Hg, respectively). The strain difference in serum MBG was investigated to determine whether genomic regions influencing MBG might be identified by genetic mapping. Quantitative trait locus mapping indicated a single locus influencing serum MBG in the region of chromosome 6q12. Homozygosity of WKY alleles at this locus was associated with increased serum MBG levels. We surveyed whole genome sequences from our SHR‐A3 and WKY lines, seeking coding sequence variation between SHR‐A3 and WKY within the mapped locus that might explain the inherited strain difference in serum MBG.ConclusionsWe identified amino acid substitution in the sterol transport protein Abcg5, present in SHR‐A3, but absent in WKY, that is a potential mechanism influencing MBG levels.

show abstract

“…40 Administration of spironolactone to these patients with resistant hypertension for 6 months in addition to the conventional triple anti-hypertensive therapy restores of NKA activity, decreased SBP and DBP, and significantly reduced PWV. These data further demonstrate the intimate relationship of MBG and arterial stiffness.…”

Section: An Age-associated Increase In Renin Angiotensin Aldosterone mentioning

confidence: 91%

“…35,36,37,38,39 Interestingly, compared to normotensive control, older patients with resistant hypertension demonstrate greater blood pressure and PWV, higher plasma MBG (an NKA inhibitor), and decreased erythrocyte NKA activity. 40 In this regard, it is of note that the increase in arterial pressure induced by a chronic high NaCl intake (i.e. salt-sensitive hypertension) in rodents is substantially reduced by an anti-MBG antibody.…”

Section: Salt-sensitive Hypertension and Agingmentioning

confidence: 99%

See 1 more Smart Citation

The Pressure of Aging

AlGhatrif

Wang²,

Федорова³

et al. 2017

Medical Clinics of North America

Self Cite

View full text Add to dashboard Cite

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and a rise of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and a rise in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age, more profoundly in men than women, likely reflecting the more pronounced aortic dilatation in men. There is an increased prevalence of salt-sensitive hypertension with advancing age, that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand, which is also linked to central arterial stiffness. Within the arterial wall, biomechanical and humoral changes are accompanied by significant biomolecular alterations producing a proinflammatory state, in which activation of angiotensin II signaling plays a pivotal role. This proinflammatory state is in origin a reparatory response to a damaged arterial wall under a pulsatile injury. However the same reparatory process results in fibrosis, which in turn worsens arterial stiffness and produce more pulsatile hemodynamics; this relationship between the pulsatile damage and proinflammatory state is best described as a feed-forward loop. Effective efforts to counter the surging epidemic of hypertension with the aging of our population should be aimed at revealing early, pre-clinical hemodynamic and arterial wall alterations, and develop interventions that halt these processes before they reach the stage the medical community defined as “disease”.

show abstract

Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

Cited by 33 publications

References 33 publications

Regulation of myofibroblast differentiation by cardiac glycosides

Regulation of myofibroblast differentiation by cardiac glycosides

Genetic Control of Serum Marinobufagenin in the Spontaneously Hypertensive Rat and the Relationship to Blood Pressure

The Pressure of Aging

Contact Info

Product

Resources

About