Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions

Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/β-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process. Non-coding RNAs regulate aortic valve calcification via Wnt pathway Calcific aortic valve disease (CAVD, a common heart condition) currently has no effective treatments. This research aimed to examine the role of non-coding RNAs (molecules that control gene activity) in CAVD, particularly circHIPK3 and miR-182-5p. Experiments were conducted on human heart valve cells and mice, showing that circHIPK3 can prevent heart valve hardening, while miR-182-5p can trigger a process that encourages hardening. The research also discovered a protein, Krm1, that can stop this hardening process. These results suggest that focusing on these non-coding RNAs and proteins could offer a new way to treat CAVD. However, more research is needed to fully comprehend these processes and their potential treatment implications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.