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1.2 Marinobufagenin (MBG), An Endogenous Steroidal na Pump Inhibitor, is Implicated in Cardiovascular Tissue Remodeling and in Pro-Fibrotic Signaling in Old Dahl Salt-Sensitive (Dahl-S) Rats

Abstract

Marinobufagenin (MBG) initiated cardiovascular pro-fibrotic pathway in experimental uremic cardiomyopathy. Fibrosis is a hallmark of aging, so we hypothesized that MBG is a key player in pro-fibrotic signaling in aging. We immunoneutralized heightened MBG levels in old (12-mo) Dahl-S with anti-MBG monoclonal antibody (OA; n = 6), and studied the pro-fibrotic gene expression in these rats in comparison to vehicle-treated 12-mo old control (OC; n = 6) and to young control (YC; 3-mo; n = 6) Dahl-S. All animals were kept on a low salt intake after weaning. Antibody was administered 3 times during 10 days to 12-mo old Dahl-S. Following 10 days of treatment, systolic blood pressure (SBP), 24-hr MBG excretion, mRNA expression (qPCR) in left ventricles (LV), and collagen and elastin abundance (histochemistry) in aortic media were assessed. In OC vs. YC, MBG level increased 3.6-folds (p<0.01), SBP elevated (175±3 vs. 117±6 mmHg; p<0.001), aortic elastin/collagen ratio decreased 3.3-fold, and expression of genes, implicated in TGFβ-signaling in LV were upregulated (TGFβ1 -3-fold; TGFβ2 -8-fold; CTGF-7.5-fold; SMAD4, SMAD5, MAPK3, and Collagen1 - 2-fold), and were down-regulated following immunoneutralization of MBG. The negative regulator of collagen1 synthesis Fli1 was 2-fold down-regulated in OC vs. YC, and restored in OA to the level of Fli1 in YC. In OA vs. OC, SBP decreased (156±5 mmHg; p<0.05), and aortic elastin/collagen ratio was normalized.

Immunoneutralization of MBG produces anti-hypertensive and anti-remodeling effects associated with normalization of gene expression implicated in TGFβ- and Fli1-pro-fibrotic pathways initiated by MBG in aged Dahl-S. Restoration of elastin/collagen ratio indicates on normalization of vascular function by anti-MBG antibody in aging.

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Fedorova, O., Grigorova, Y., Wei, W. et al. 1.2 Marinobufagenin (MBG), An Endogenous Steroidal na Pump Inhibitor, is Implicated in Cardiovascular Tissue Remodeling and in Pro-Fibrotic Signaling in Old Dahl Salt-Sensitive (Dahl-S) Rats. Artery Res 8, 122 (2014). https://doi.org/10.1016/j.artres.2014.09.051

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  • DOI: https://doi.org/10.1016/j.artres.2014.09.051