MicroRNAs Contribute to Angiotensin II‐Mediated Regulation of Transmural Electrical Remodeling in the Heart

Abstract

Activation of the local renin angiotensin system (RAS) by Angiotensin II (Ang II) in the heart induces electrical remodeling, including inhibition of transient outward potassium current Ito, prolongation of the action potential, and increased contractility. Moreover, the long‐term, persistent action of Ang II causes cardiac hypertrophy and heart failure (anatomic remodeling). The transmural gradient of multiple ionic currents, including Ito, is involved in Ang II‐mediated electrical remodeling. Differential expression of miRNAs may play a critical role in the signaling cascade for Ang II‐induced electrical remodeling. To investigate this hypothesis, a detailed analysis of potential miRNAs involved in Ang II‐mediated modulation was undertaken using miRNA microarray analysis of endocardium and epicardium tissue from the left ventricle of a Sprague‐Dawley rat. The left ventricular tissue samples were treated with either Ang II (2mM) or Losartan (2mM) to further screen for differences in miRNA expression between EPI and ENDO. Although forty‐nine miRNAs were expressed in a significant gradient between EPI and ENDO, only miR‐385‐5p and miR‐301a‐3p were found to exhibit similar expression patterns as Ito when modulated by Ang II. Taken together, these data suggest that miR‐382‐5p and miR‐301a‐3p could contribute to Ang II‐mediated transmural electrical remodeling and may provide a potential target for the study of heart failure mechanisms and therapeutic application.Expression of miR‐382‐5p and miR‐301a‐3p in EPI and ENDO.A. Left: miR‐382‐5p is upregulated in EPI compared to ENDO. Middle: miR‐382‐5p is upregulated in EPI compared to EPI with Ang II. Right: miR‐382‐5p is downregulated in ENDO compared to ENDO with Losartan.B. Left: miR‐301a‐3p is downregulated in EPI compared to ENDO. Middle: miR‐301a‐3p is downregulated in EPI compared to EPI with Ang II. Right: miR‐301a‐3p is upregulated in ENDO compared to ENDO with Losartan.Figure 1Schematic diagram of Ang II‐mediated anatomic and electrical remodeling in the heart. The transmural distribution of Ang II causes the transmural gradient of ionic currents including Ito, Ip, ICaL and ICaTL (electrical remodeling). Under long term imbalances between volume load and maximum contractile strength, the heart undergoes hypertrophy and heart failure (anatomic remodeling). We hypothesize that miR‐382‐5p and miR‐301a‐3p contribute to Ang‐II mediated remodeling of the heart.Figure 2