A Novel circRNA Highlights a Path to Cardiac Hypertrophy in Spontaneously Hypertensive Rats.

Abstract BackgroundCardiac hypertrophy can be considered a maladaptive response which in many cases results in heart failure and sudden death. Genetic predisposition to cardiac hypertrophy is ill-defined, but current research has given credence to a role of non-protein-coding RNAs in the development of cardiac hypertrophy.ResultsWe used microarrays, RNA-Seq and quantitative genetics with the spontaneously hypertensive, SHR (SHR/OlaIpcv) rat strain, the normotensive Brown Norway (BN-Lx/Cub) rat strain, and a recombinant inbred (RI) panel of rats (HXB/BXH) derived from these strains to examine the areas of the genome associated with cardiac hypertrophy. We identified circular (circ) RNAs coded within these areas. Of the 122 differentially expressed circRNAs in left ventricle of SHR and BN-Lx rats, three were transcribed from areas corresponding to the QTLs we identified for cardiac hypertrophy using the HXB/BXH rat panel. We then identified microRNAs which are “sponged” by the circ RNAs and the mRNAs which are destabilized by the microRNAs. 265 miRNAs could be identified as targets for the three circRNAs. We focused on the four miRNAs that were also differentially expressed between SHR and BN-Lx rats. One of the miRNAs (Mir-210-5p) was a target of the differentially expressed circ H2afy and circ H2afy was located within the QTL on Chr 17 (genome wide p-value = 0.011). Mir-210-5p has a binding site on the 3’ UTR of DR6, which is differentially expressed and in turn controls the expression level of NFκB. NFκB is an important component of the oxidative stress response leading to hypertrophy.ConclusionsOur work identified a novel circRNA that may be the mediator of a cascade of events that influence a cardiac hypertrophy phenotype. The circRNA and miRNA which we identified may become useful as markers of the risk for cardiac hypertrophy.