Marinobufagenin as a therapeutic target

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Human study: Eleven patients with PE (mean BP 124 +/- 4 mmHg; age 29 +/- 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 +/- 2 mmHg; controls) were enrolled in the clinical study. Results: PE was associated with a higher placental MBG (0.04 +/- 0.01 vs. 0.49 +/- 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 +/- 0.1 vs. 1.6 +/- 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 +/- 0.2 vs. 1.5 +/- 0.2 umol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. Conclusion: These results demonstrate (i) that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries, and (ii) that MBG is a potential therapeutic target in PE. Animal study: In addition, we demonstrated that high (HS) salt intake stimulates MBG production and activates vascular transforming growth factor-beta (TGF-beta) profibrotic signaling in young normotensive rats, and that these changes can be reversed by reducing HS intake to a normal salt level. Three-month old male SpragueDawley rats received normal salt diet for 8 weeks (0.5% NaCl), or HS diet for 8 weeks (4% NaCl), or HS diet for 4 weeks followed by a normal salt diet for 4 weeks, n = 8/group. Systolic BP (SBP), pulse wave velocity (PWV; a marker of aortic stiffness), MBG excretion, aortic collagen 1a2, collagen 4a1, TGF-beta, Smad2, Smad3, Fli-1 mRNA, and total collagen abundance were measured at baseline, and on week 8. Statistical analysis was performed using one-way ANOVA. SBP was not affected by HS diet, and MBG and PWV were higher after 8 weeks of a HS diet: MBG: 180 +/- 19 pmol/24 h/kg vs. 103 +/- 19 pmol/24 h/kg, HS vs. baseline, p < 0.05; PWV: 4.7 +/- 0.2 m/s vs. 2.7 +/- 0.2 m/s, HS vs. baseline, p < 0.05. HS intake was associated with an increase in aortic Col1a2 (80%), Col4a1 (50%), Tgfb1 (30%), Smad2 (30%) and Smad3 (45%) mRNAs, and aortic wall collagen abundance (180%) vs. age-matched normal salt (all p < 0.05). Normal salt diet following HS diet downregulated HS-induced factors: the MBG level was twofold lower, p < 0.01, PWV was 3.7 +/- 0.3 m/s vs. 4.7 +/- 0.2 m/s (p < 0.05), aortic wall Tgfb1, Col1a2, Col4a1, Smad2, Smad3 mRNAs, and collagen abundance were reversed by salt reduction to the baseline levels (p < 0.05). HS diet was associated with an activation of TGF-beta signaling, aortic fibrosis and aortic stiffness accompanied by an MBG increase in the absence of SBP changes in young normotensive rats. The reduction of dietary salt following HS decreased MBG, PWV, aortic wall collagen and TGF-beta. Conclusion: HS-induced aortic stiffness in normotensive animals occurred in the context of elevated MBG, which may activate SMAD-dependent TGF-beta pro-fibrotic signaling. This data suggests that a decrease in salt consumption could help to restore aortic elasticity and diminish the risk of cardiovascular disease by reducing the production of the pro-fibrotic marker MBG.