Genetic and epigenetic changes associated with polygenic left ventricular hypertrophy

Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.Doctor of Philosoph