Cardiac fibrosis, a pathological consequence of cardiac injury, can be manifest either as localized scar or more diffuse interstitial fibrosis. The cells responsible for cardiac fibrosis are cardiac fibroblasts, which numerically are the most prevalent cells in the heart. Cardiac fibroblasts are regulated by hormones, many of which act via plasma membrane receptors, including ones that are linked to heterotrimeric G proteins and G-protein- regulated effectors. One such effector, adenylyl cyclase, catalyzes the formation of cyclic AMP from ATP and is the focus of this proposal. Cyclic AMP has anti-fibrotic actions that include inhibition of the transformation of """"""""resting"""""""" cardiac fibroblasts to pro-fibrogenic myofibroblasts. This proposal will test several hypotheses related to the ability of increased cyclic AMP formation, produced by enhanced expression of adenylyl cyclase-6 (AC-6), to alter biochemical and functional activities of cardiac fibroblasts. Studies will be conducted using primary cultures of cardiac fibroblasts and, in addition, will involve the use of an animal model (angiotensin infusion in rats and mice) that produces cardiac fibrosis. The experiments focus on AC-6 with an emphasis on its compartmentation with proximal and distal signaling components as well as impact of increased AC-6 expression on the fibrotic response, as assessed by several phenotypic characteristics. The results should provide proof-of-principle data regarding the potential for therapeutic targeting of cardiac fibroblasts by gene transfer with AC-6 and potentially other AC isoforms. It is likely that targeting of AC-6 to cardiac myocytes via intracoronary delivery of recombinant viral vectors (Project 1) will increase AC-6 expression in fibroblasts. The general hypothesis of Project 2 is that increased expression of AC-6 in cardiac fibroblasts will alter the fibrotic response and favorably modify cardiac remodeling to improve cardiac function in the failing heart.
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