Markedly Reduced Myocardial Expression of γ-protocadherins and Long Non-coding RNAs in Patients with Heart Disease

Background: Adverse cardiac remodeling and tissue damage following heart disease is strongly associated with chronic low grade inflammation. The mechanisms underlying persisting inflammatory signals are not fully understood, but may involve defective and/or non-responsive transcriptional and post-transcriptional regulatory mechanisms. In the current study, we aimed to identify novel mediators and pathways involved in processes associated with inflammation in the development and maintenance of cardiac disease.

Methods And Results: We performed RNA sequencing analysis of cardiac tissue from patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) and compared with control tissue from multi-organ donors. Our results confirmed previous findings of a marked upregulated inflammatory state, but more importantly, we found pronounced reduction of non-protein coding genes, particularly long non-coding RNAs (lncRNA), including several lncRNAs known to be associated with inflammation and/or cardiovascular disease. In addition, Gene Set Enrichment Analysis revealed markedly downregulated microRNA pathways, resulting in aberrant expression of other genes, particularly γ-protocadherins.

Conclusions: Our data suggest that aberrant expression of non-coding gene regulators comprise crucial keys in the progression of heart disease, and may be pivotal for chronic low grade inflammation associated with cardiac dysfunction. By unmasking atypical γ-protocadherin expression as a prospective genetic biomarker of myocardial dysfunction, our study provides new insight into the complex molecular framework of heart disease. Creating new approaches to modify non-coding gene regulators, such as those identified in the current study, may define novel strategies to shift γ-protocadherin expression, thereby normalizing part of the molecular architecture associated with heart disease.