Abstract-The evolutionary conserved Wnt signaling pathway regulates cardiogenesis. However, members of the Wnt pathway are also expressed in the adult heart. Although Wnt-signaling is quiescent under normal conditions, we noticed activation on pathological stress of the heart, such as chronic afterload increase. To examine the role of Wnt signaling on the postnatal heart, we modified the expression and function of the Wnt regulator dishevelled 1 (Dvl-1) both in transgenic mice with cardiac-specific overexpression of Dvl-1 (Dvl-1-Tg) and in cultured cardiac myocytes. Dvl-1-Tg mice (3 months) had severe cardiac hypertrophy (heart weight:body weight ratio: 5.2Ϯ0.3 mg/g wild-type [WT] versus 6.4Ϯ0.7 mg/g Dvl-1-Tg; PϽ0.01), an increase in cardiomyocyte size (86% increase in Dvl-1-Tg compared with WT; PϽ0.01) and marked raise of atrial natriuretic factor expression (12-fold increase versus WT; PϽ0.01). Hypertrophy was associated with left ventricular dilatation in Dvl-1-Tg and a reduction of ejection fraction (4.4Ϯ0.1 mm versus 5.5Ϯ0.2 mm, 80Ϯ2% and 43Ϯ4% in WT versus Dvl-1-Tg, respectively; PϽ0.01). Transgenic animals died prematurely before 6 months of age. Both canonical as well as noncanonical Wnt signaling branches were activated in the Dvl-1-Tg animals. Small interfering RNA-mediated depletion of Dvl-1 was used to further characterize the role of Dvl-1 in cardiac myocytes. Whereas baseline parameters were unaltered, -adrenergic hypertrophic response was abrogated in Dvl-1 knockdown cardiac myocytes, indicating a mandatory role in -adrenergic stimulation. Therefore, activation of Wnt signaling is sufficient and critical for the induction of myocardial hypertrophy and cardiomyopathy. Key Words: Wnt signaling Ⅲ cardiac hypertrophy Ⅲ experimental heart failure A fter conditions of increased wall stress, the myocardium may adopt by a process called remodeling. Left ventricular remodeling is considered to be a maladaptive process characterized by myocyte hypertrophy, an increase in myocardial fibrosis, and left ventricular dilatation. Remodeling may induce clinically overt heart failure and contributes to increased mortality after myocardial infarction. Other than standard heart failure medications, there are no treatment options available targeted to maladaptive remodeling. On pathological stress, the heart reactivates a number of signaling pathways, which traditionally were thought to be operational primarily in the developing organism. The Wnt pathway is an evolutionary conserved signaling mechanism with a critical function in tumor growth 1 and cardiogenesis. 2,3 However, members of the Wnt pathway are also expressed in the normal adult heart. 4 -7 Thus, for example, the Frizzled (Fz) class of cell surface receptors of Wnt proteins, including Fz1 and Fz2, is expressed in human myocardium. 7 In infarcted hearts, Fz2 expression is considerably enhanced, 8 and in failing ventricles of humans, mRNA levels of secreted Fz-related proteins 3 and 4, which are endogenous Wnt antagonists, are elevated, leading to attenuat...
