Local, fibroblast-specific cardiac actions of the natriuretic peptides ANP, BNP and CNP

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Cardiac remodeling in response to pressure overload or ischemia involves not only cardiomyocyte alterations but also activation of fibroblasts to myofibroblasts and excessive collagen accumulation contributing to impaired cardiac function. These changes are modulated by mechanical forces and neurohumoral factors. Among these factors are the natriuretic peptides atrial and B type (ANP and BNP, mainly released from myocytes) as well as C type NP (CNP, secreted by endothelial and infiltrating inflammatory cells). NPs signal through specific transmembrane guanylyl cyclase (GC) receptors and cyclic GMP as second messenger, namely GC A (the receptor shared by ANP and BNP) and GC B (for CNP). Our previous experimental studies in genetic mouse models showed that ANP and BNP may act as key local antihypertrophic and proangiogenic factors during cardiac remodeling. The cardiac role of CNP is less well understood. Its GC B receptor is expressed in all resident myocardial cells (fibroblasts, cardiomyocytes and vascular cells). Administration of synthetic CNP greatly attenuates cardiac hypertrophy, fibrosis and contractile dysfunction in mice with experimental pressure overload or ischemia. Notably, our ongoing studies of a novel genetic mouse model with cardiomyocyte restricted deletion of GC B indicate that myocytes are only partly involved in these protective CNP actions. In vitro, synthetic NPs (CNP more than ANP) counterregulate the stimulatory effects of TGF on fibroblast proliferation, differentiation and collagen secretion. To dissect the fibroblast actions of endogenous local NPs in vivo, here we generate new genetic models with induced, fibroblast specific deletion of either GC A or GC B in adult mice for studies of the impact on hypertensive or ischemic heart disease.