Abstract 446 <P><SPAN>Identification of a potential roquin-miR-34c-3p axis in post-infarct remodeling that cannot be affected by conditioning</SPAN></P>

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Identification of a potential roquin-miR-34c-3p axis in post-infarct remodeling that cannot be affected by conditioning
N. Itani¹, R. Schreckenberg¹, R. Schulz¹, K.-D. Schlüter¹
¹Physiologisches Institut, Justus-Liebig-Universität Giessen, Gießen;
Ischemic pre- and post-conditioning affects infarct sizes but the impact on post-infarct remodeling is less clear. Post-Infarct remodeling is triggered by alterations in protein expression, depending on transcriptional activation generating mRNA that is translated into protein and protein degradation by ubiquitination. Therefore, mRNA stability is important for this process. mRNA stability is regulated by micro-RNAs (miRs). miRs bind to mRNAs at specific binding sites due to sequence homology and thereby induce mRNA degradation. However, the stability of miRs is regulated by proteins vice versa. In this context, roquins have recently been identified. Roquins bind to specific miRs and destabilize miRs. It is known from immune cells that roquin targets miRs that control the activity of the AKT-Pathway that is mandatory for hypertrophic growth in cardiomyocytes. Alterations in roquin expression should therefore affect post-infarct remodeling. Here, we investigated the effect of ischemia-reperfusion and conditioning on post-infarct mRNA expression of roquins. Roquins were down-regulated in post-infarct hearts (left ventricle, seven days post infarction) and this was not affected by either pre- or post-conditioning. To evaluate a possible functional consequence we screened correlation with miRs expression to identify potential targets of roquins in the heart. Among 359 miRs that were constitutively expressed in the left ventricle, miR-34c-3p was identified as the miR with the best inverse correlation to roquin expression. Moreover, conditioning did neither affect the down-regulation of roquin nor the up-regulation of miR-34c-3p. In addition, roquin mRNA is highly co-regulated with the expression of Kcnh5 and AT2 receptors whereas miR-34c-3p is inversely correlated with the expression of these two mRNAs. The data are in accordance with the hypothesis that down-regulation of roquins by ischemia/reperfusion allows up-regulation of miR-34c-3p that then targets AT2 receptors and Kcnh5. Furthermore, when roquin expression was down-regulated in isolated and cultured adult rat ventricular cardiomyocytes, an increased amount of AKT phosphorylation was seen, indicating de-inhibition of this pathway by down-regulation of roquins. In summary, we provide evidence for a roquin-miR-34c-3p axis that cannot be affected by conditioning. The lack of efficiency of conditioning to affect the expression of roquins gives us a hint to understand the low functional long-term improvement of conditioning in rat hearts irrespectively of the infarct size sparring effect.
https://dgk.org/kongress_programme/jt2023/aP1771.html