ANP Modulates Cardiac Remodeling via Cardiac Fibroblasts

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Atrial natriuretic peptide (ANP) is a well known component of the fetal gene program that is overexpressed in adult heart under stress conditions. Yet little attention has been devoted to the function of ANP in the stressed/hypertrophic heart. The current application will test the hypothesis that ANP has direct anti-growth and anti-fibrogenic effects that oppose the pro-fibrogenic actions of transforming growth factor (TGF)-beta and angiotensin II (ANGII), which are known to be overexpressed in heart under stress conditions, by interrupting their signaling cascades. We have shownthat, compared to nontransgenic (NTG) controls, mice with homozygousdisruption of the ANP gene (Nppa-/-) exhibit cardiac enlargement at baseline and exaggerated cardiac remodeling/fibrosis, as well as an early transition to failure, in response to transverse aortic constriction (TAC)-induced pressure overload stress. Preliminary studies revealed remarkable increases in myofibroblast transformation and expression of extracellular matrix (ECM) molecules in hearts of Nppa-/- mice subjected to TAG. We have also demonstrated that TAC-induced cardiac remodeling and fibrosis are abolished in mice that express an inducible dominant negative mutation of the TGF-beta receptor type II gene (DriTGFbRIl), andthus do not respond to TGF-beta signaling. Most recently, we have made the exciting preliminary observation that ANP signaling inhibits TGF-beta-induced nuclear translocation of phosphorylated-SmadS in mouse cardiac fibroblasts (CFs), defining for the first time a precise molecular mechanism by which ANP signaling may protect against cardiac remodeling/fibrosis and failure in response to hemodynamic stress. The Aims of this proposal are: 1)To establish the phenotypes of Nppa-/-, DnTGFbRII and control NTG mouse hearts under resting conditions and at various phases (acute stress, early compensatory stage of fibrosis and remodeling, and late decompensate/transition stage to failure) during pressure overload stress following TAG. This Aim will provide the first rigorous in vivo test of the role of TGF-beta signaling in mediating pressure overload-induced LV fibrosis/remodeling and of ANP in modulating these processes. 2) Using isolated CFs as an in vitro model, to define the intracellular signaling mechanisms leading to pro-fibrogenic/growth factor-stimulated CF proliferation/transformation andECM expression. This Aim will provide a rigorous test of the hypothesis that ANP signaling has negative, and TGF-beta (and/or ANGII) signaling has positive stimulatory effects on these processes. ANP and/or components of its signaling pathwaywill be used to define the specific site(s) at which the ANP cascade intercepts pro-fibrogenic/growth factor signaling, thus inhibiting phenotypic transformation of CFs andECM production. These mechanistic studies will provide a more rational basis for therapeutic intervention in patients with cardiac dysfunction/failure, many of whom have decreased levels of ANP.