Abstract 603: Silencing Of PKG1 Gene Mimics Effect Of Aging And Sensitizes Vascular Smooth Muscle Cells To Pro-fibrotic Effect Of Cardiotonic Steroids
Marinobufagenin (MBG), an endogenous Na/K-ATPase inhibitor and a vasoconstrictor, induces vascular fibrosis via PKC-dependent inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen synthesis. In vascular smooth muscle cells (VSMC), ANP, via cGMP/PKG1 dependent mechanism, reduces sensitivity of Na/K-ATPase to MBG. Because vascular fibrosis is a hallmark of cardiovascular aging, we hypothesized that VSMC from aged rats, in which cGMP/PKG-dependent signaling is down-regulated, would exhibit heightened sensitivity to the pro-fibrotic effect of MBG.
In primary culture of VSMC from thoracic aorta from young (3 month old) rats, 1 nmol/L MBG inhibited Na/K-ATPase by 15%, and induced a 60% down-regulation of Fli-1 and a concomitant 50% increase in the levels of collagen-1. Alpha-ANP (1 nmol/L) blocked these effects.
In VSMC from aged (24 months old) rats levels of PKG1 and Fli-1 in VSMC were markedly reduced, while PDE-5 was markedly upregulated. MBG (1 nmol/L) inhibited Na/K-ATPase by 26%, suppressed Fli-1 two-fold, and increased level of collagen-1 more than two-fold (P<0.01). Unlike that in young rats, alpha-ANP failed to oppose these effects of MBG in aged animals.
Silencing of the PKG1 gene in VSMC from young rats produced a marked increase in the sensitivity of VSMC to the pro-fibrotic effect of MBG; 1 nmol/L MBG increased levels of collagen-1 2.5-fold (P<0.01).
These results demonstrate that age-associated reduction in vascular PKG1 levels and resultant decline in cGMP signaling sensitize VSMC to pro-fibrotic effect of MBG. Silencing of PKG1 in VSMC from young rats mimics these effects of aging.
- © 2012 by American Heart Association, Inc.