Wnt Signaling Pathway in Right Ventricular Remodeling

Rationale: Right ventricular (RV) remodeling comprises multiple adaptation mechanisms to increased pressure- or volume-overload, which in concert determine RV performance as well as clinical outcome in patients with pulmonary hypertension. It is believed that in the pressure-overloaded hearts a re-expression of neonatal genes, e.g. Wnt signaling molecules is triggered.

Methods and Results: In our study we employed two animal models of RV remodeling: monocrotaline (MCT) model of pulmonary hypertension and pulmonary artery banding (PAB) model. To characterize global expression changes that occurred in our animal model RVs, microarray experiments were performed. Comparative, microarray based transcriptome analysis of RV remodeling identified upregulation of Frizzled receptors in the remodeled RVs, suggesting the involvement of Wnt canonical pathway. In accordance, we found significant upregulation of several Wnt signaling molecules including: β-catenin, GSK3ß and Frizzled receptors in the RVs as well as in the primary cardiac fibroblasts (CFs) isolated from PAB and MCT rats. Further addressing the influence of Wnt signaling on CFs, we found that stimulation of RCFs with Wnt3a resulted with increased collagen expression and ß-catenin knockdown caused decreased collagen synthesis. Similarly, Wnt3a induced CFs proliferation and ß-catenin knockdown caused decreased proliferation rates of these cells. Importantly, pulmonary artery banding of BAT-Gal mice containing a beta-catenin-activated LacZ reporter, resulted in increased ß-catenin activation in remodeled RVs, as compared to sham operated animals.

Conclusions: We can conclude that Wnt signaling is important for the development of RV remodeling and may eventually offer innovative treatment strategies.