Secreted-Frizzled-Related Protein 5 Modulates Calcium Handling in Human Ipsc-Cardiomyocytes

Abstract

End-stage heart failure caused by myocardial injury is a leading cause of death in the developed world, with high prevalence and poor prognosis. Current therapies focus on attenuating cardiac remodeling after a cardiovascular event such as myocardial infarction or pressure overload, but no therapy is currently available to halt or reverse disease progression. Recent studies have suggested a cardioprotective function of the Wnt5a inhibitor secreted frizzled-related protein 5 (SFRP5) in preventing adverse cardiac remodeling. However, until now, the underlying molecular mechanisms of SFRP5 treatment in the human heart are not well understood. In this study, we investigated the mechanistic and functional consequences of SFRP5 by establishing knockout and overexpression models in human iPSC-derived cardiomyocytes. Transcriptome profiling and deep pathway analysis revealed an involvement of SFRP5 in the regulation of calcium handling, cardiac contraction, and apoptosis. Functional analysis of iPSC-cardiomyocytes by live-cell calcium imaging confirmed the regulatory role of SFRP5 on calcium homeostasis. Our study uncovered a novel role of SFRP5 as a modulator of calcium handling, providing a deeper molecular understanding of the cardioprotective role of SFRP5 in the human heart.

Note:
Funding declaration: This work was supported by the German Research Foundation (DFG): project number 193793266, Collaborative Research Centre 1002, D01, D04 and S01 to K.T., G.H., and L.C.; project number 390729940, Germany’s Excellence Strategy - EXC 2067/1 to K.T., G.H., and L.C.; by the German Federal Ministry of Education and Research (BMBF)/German Center for Cardiovascular Research (DZHK) to G.H. and L.C., and by the Kaltenbach Doctoral Fellowship of the German Heart Foundation (Deutsche Herzstiftung) to F.W.

Conflict of Interests: None.

Ethical Approval: The study was approved by the Ethics Committee of the University Medical Center Göttingen (approval number: 10/9/15) and carried out in accordance with the approved guidelines. Written informed consent was obtained from all participants prior to the participation in the study.

Keywords: AAV delivery, cardiac remodeling, calcium handling, cardiomyocytes, CRISPR/Cas9, iPSCs, SFRP5, Wnt5a signaling