A monoclonal antibody to a steroidal endogenous Na/K-ATPase ligand, marinobufagenin, reverses expression of pro-fibrotic genes in aged rats

Thursday, November 07, 2013 — Poster Session II
12:00 p.m. – 2:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIA	PHARM-4

Authors

O. V. Fedorova
V. Shilova
V. Zernetkina
Y. Zhang
C.A. Marshall
E. Lehrmann
K.G. Becker
E.G. Lakatta
A.Y. Bagrov

Abstract

Cardiovascular fibrosis is a hallmark of aging. An endogenous Na/K-ATPase ligand, marinobufagenin (MBG) plays a central role in cardiac fibrosis in experimental uremic cardiomyopathy via Fli-1-dependent pro-fibrotic signaling. We hypothesized that MBG is implicated in aging-associated fibrosis. To test our hypothesis we studied effect of immunoneutralization of heighten MBG levels in old (24-mo) Sprague-Dawley rats on the expression of pro-fibrotic genes vs. those in young (3-mo; n=6) controls. One week following a single administration to aged rats of an anti-MBG monoclonal antibody (n=6) or vehicle (n=6), the expression of genes implicated in pro-fibrotic signaling (qPCR) were assessed in left ventricular (LV) myocardium. Plasma MBG was elevated two-fold in old vs. young rats in the absence of blood pressure changes, and was accompanied by upregulation of genes implicated in TGFβ-signaling: TGFβ1, 3-fold; CTGF1, 6-fold; SMAD3, 2-fold; collagen-1, 2.6-fold. Expression of these genes was significantly suppressed following immunoneutralization of MBG. The expression of Fli-1, a negative regulator of collagen-1 synthesis, was reduced by 3-fold in old vs. young rats. Anti-MBG antibody restored Fli-1 levels in old rats. The age-associated increase in MBG participates in pro-fibrotic signaling linked to advancing age, and cross-talk between TGFβ-dependent and Fli-1-dependent pro-fibrotic pathways underlies this MBG effect.