All ETDs from UAB

Advisory Committee Chair

Suzanne Oparil

Advisory Committee Members

Susan Bellis

Jedwin Blalock

Gilbert Perry

Joanne Murph-Ullrich

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Pressure overload stress (eg. hypertension or aortic stenosis) results in excessive cardiac fibrosis, changes in left ventricular (LV) geometry, and disruption of LV contractility, ultimately leading to heart failure. We hypothesize that transforming growth factor-beta (TGF-beta), a pro fibrogenic factor, and atrial natriuretic peptide (ANP), an anti fibrogenic factor, interact directly in a counterregulatory manner to balance the production of extracellular matrix (ECM) under pressure overload induced cardiac stress or hypoxia-induced pulmonary vascular adaptation. In this report, we examine structural and functional responses of the intact heart to pressure overload stress in vivo. We then utilize isolated rat pulmonary artery smooth muscle cells (PASMC) and mouse cardiac fibroblasts (CF) to delineate on the cellular level the counterregulatory roles of TGF-beta and ANP/cGMP/protein kinase G (PKG) in determining stress responses in vitro. First, we utilized a DnTGFbetaRII mouse model to define the contribution of TGF-beta signaling to the phenotype of cardiac remodeling and fibrosis in response to pressure overload. We demonstrated that inhibition of TGF-beta signaling attenuates pressure overload-induced interstitial non-myocyte proliferation and collagen deposition with subsequent development of LV dilation and systolic dysfunction. Second, we demonstrated that ANP has an anti-fibrogenic effect on PASMC treated with TGF-beta. ANP and cGMP suppressed the TGF-beta stimulated ECM gene expression by interfering with Smad signaling through a protein kinase G (PKG)-dependent mechanism. The most striking finding of this study is that ANP and cGMP inhibit TGF-beta1-induced nuclear translocation of pSmad2 and pSmad3, but not the phosphorylation of Smad2 and Smad3 in PASMCs, thus defining a novel molecular mechanism by which ANP signaling intercepts the TGF-beta signaling pathway and blocks TGF-beta-induced ECM expression. Finally, we demonstrated a precise site of "molecular merging" of pro-fibrogenic (TGF-beta/Smad) and anti-fibrogenic (ANP/cGMP/PKG) pathways in CFs: PKG induced hyper-phosphorylation of Smad3 protein, with resultant failure of nuclear translocation of pSmad3 and consequent inhibition of TGF-beta/Smad induced ECM gene expression. Thus, we have demonstrated cross talk between ANP and TGF-beta signaling pathways in CFs in vitro such that ANP/cGMP, through a PKG dependent mechanism, block induction of ECM expression by TGF-beta1.



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