Genetic Analysis of Connective Tissue Growth Factor as an Effector of Transforming Growth Factor Signaling and Cardiac Remodeling

Thematricellular secreted protein connective tissue growth factor (CTGF) is upregulated in response to cardiac injury or with transforming growth factor (TGF-) stimulation, where it has been suggested to function as a fibrotic effector. Here we gener-ated transgenic mice with inducible heart-specific CTGF overexpression, mice with heart-specific expression of an activated TGF-mutant protein, mice with heart-specific deletion of Ctgf, andmice in which Ctgfwas also deleted from fibroblasts in the heart. Remarkably, neither gain nor loss of CTGF in the heart affected cardiac pathology and propensity toward early lethality due to TGF- overactivation in the heart. Also, neither heart-specific Ctgf deletion nor CTGF overexpression altered cardiac re-modeling and function with aging or after multiple acute stress stimuli. Cardiac fibrosis was also unchanged bymodulation of CTGF levels in the heart with aging, pressure overload, agonist infusion, or TGF- overexpression. However, CTGFmildly al-tered the overall cardiac response to TGF-when pressure overload stimulation was applied. CTGF has been proposed to func-tion as a critical TGF- effector in underlying tissue remodeling and fibrosis throughout the body, although our results suggest that CTGF is of minimal importance and is an unlikely therapeutic vantage point for the heart. Heart failure is associatedwith structural alterations of the ven-tricles that include hypertrophy and/or elongation of individ-ual cardiacmyocytes as well asmyocardial fibrosis (1).Myocardial fibrosis involves an increase in extracellular matrix (ECM) depo-sition that adversely affects the function of the heart by disruptin