Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Investigating the role of circCHPC in pathological cardiac hypertrophy
W. Pan1, K. Xiao1, I. Riedel1, S. Chatterjee1, C. Bär1, T. Thum1
1Institut für Molekulare und Translationale Therapiestrategien, OE-8886, Medizinische Hochschule Hannover, Hannover;
Background:
Heart failure (HF) is a major public health problem worldwide. Due to the unhealthy lifestyle and the global increase in aging, the morbidity and mortality of cardiovascular disease are continuously rising. Therefore, exploring novel preventive and therapeutic approaches to HF is urgently needed. Circular RNAs (circRNAs) are covalently closed RNA molecules formed by back-splicing of mRNA precursors and are characterized by structural stability, high conservation, tissue-specific, and development-stage-specific expressions. Investigation of the putative function and mechanism of circRNA could provide new targets for the development of potential therapeutic strategies for the treatment of cardiovascular disease.
 
Aim:
The main objective is to identify and investigate the function of circRNAs in cardiac pressure overload leading to pathological left ventricular hypertrophy with the ultimate goal of exploring the functions and mechanisms of these candidates as a potential treatment option.
 
Methods and Results:
Through Next Generation RNA sequencing and circRNA profiling of mouse hearts with pressure overload-induced cardiac hypertrophy, we identified circCHPC (Cardiac Hypertrophy Protection CircularRNA). We first validated expression of circCHPC by RT-qPCR in additional low-gradient pressure-overload mouse models and found robust time-dependent downregulation of circCHPC in left ventricular hypertrophy tissues. Of note, the same downregulation can be observed in cultured mouse or rat cardiomyocytes after hypertrophic stimulation with Leukemia inhibitory factor (LIF), while the expression of the linear transcript of the CHPC hostgene was unchanged over time pointing toward a specific circCHPC regulatory mechanism during cardiac disease. CircCHPC is enriched in the heart and more specifically in cardiomyocytes. Of translational importance, the conserved circCHPC could also be found to be highly expressed in human iPSC-derived cardiomyocytes. To investigate a potential functional role of circCHPC in cardiomyocytes, we designed a set of siRNAs targeting the backsplicing site of CHPC to inhibit the circular but not the linear transcript. A knockdown of ~50% was achieved which resulted in a robust upregulation of hypertrophic marker genes, such as ANP, BNP and MCIP1.4 concomitant with an increased in cardiomyocyte cell sizes. Based on these results, we are currently testing AAV-based circCHPC overexpression in in vitro/in vivo cardiac hypertrophy models to address the therapeutic value of circCHPC in cardiac hypertrophy and cardiac remodeling. 
 
Conclusion:
Our results suggest that CircCHPC could represent a novel therapeutic or preventive target for the treatment of cardiac hypertrophy and heart failure.

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