Background: An increased afterload of the right ventricle (RV) can be experimentally induced by mechanic obstruction of the RV outflow via pulmonary artery banding, resulting in RV remodeling. Hypoxia has been reported to be involved in the development of right ventricular failure (RVF). One of the proteins regulating the hypoxic response is the ubiquitin E3 ligase SIAH2 (seven in absentia 2), but its impact on RV remodeling is unknown.

Objectives: The role of SIAH2 was investigated in Siah2^-/- mice in a model of RV hypertrophy (RVH) induced by pulmonary artery banding (PAB).

Methods: Cardiac remodeling was characterized by echocardiography, hemodynamic measurements and histology. Isolated cardiac fibroblasts were utilized in functional studies. The interaction of SIAH2 with potential targets was characterized by immunoprecipitation (IP) and loss of function studies in fibroblast and HEK293 cells.

Results: Siah2^-/- mice were largely protected from RV hypertrophy and RV fibrosis induced by PAB. No such changes were observed in the LV. Reduced fibrosis in Siah2-deficient PAB animals was due to a strongly increased anti-fibrotic Apelin signaling. We report the novel observation, that the apelin receptor (APJ) is directly targeted by SIAH2, resulting in its ubiquitination and proteasomal degradation. In Siah2-deficient fibroblasts APJ is stabilized, associated with decreased proliferation, migration and lower expression of pro-fibrotic genes.

Conclusions: SIAH2 promotes cardiac fibrosis in response to RV overload induced by PAB. Understanding the precise role of SIAH2 may provide novel therapeutic targets to interfere with the development of cor pulmonale.