Anti-fibrotic effects of adenylyl cyclase in the heart : implications for connective tissue remodeling by cardiac fibroblasts

Cardiac fibroblasts (CF) are the most abundant cell type in the heart and are responsible for extracellular matrix (ECM) homeostasis and repair in response to cardiac injury. Following myocardial insult, exaggerated or maladaptive production of ECM material results in myocardial stiffening and decreased cardiac relaxation, ultimately leading to diastolic heart failure. A key component of increased collagen production by CF is their transformation from quiescent fibroblasts, into activated myofibroblasts, which are characterized by expression of a -smooth muscle actin (aSMA) and an increased collagen production capacity. Adenylyl cyclases (AC) are membrane- bound proteins that catalyze conversion of ATP to cyclic AMP (cAMP), a ubiquitous second messenger that influences growth, death, and differentiated cellular functions. Previous reports indicate that AC activation, or increases in cAMP, inhibit collagen production by CF, however no studies have examined the role of AC in CF function after myocardial infarction (MI) or examined the effects of AC activation on cardiac myofibroblast formation. In this thesis, I investigated AC function by CF isolated from adult rats after MI and conducted subsequent studies to determine the effects of AC activation and overexpression on myofibroblast transformation and collagen production. Furthermore, I examined the cellular compartmentation of AC with other catalytic and structural molecules in CF in order to elucidate the cellular mechanisms by which cAMP regulates fibroblast-myofibroblast transformation and collagen production