Role and mechanism of piR-0228 targeting RIPK1 to regulate vascular remodeling and aortic dissection

The diagnosis and management of aortic dissection (AD), a critical cardiovascular disease (CVD), remains significant challenges in clinical practice. PIWI-interacting RNAs (piRNAs), a newly discovered class of non-coding small RNAs, play key regulatory role in various CVDs. However, the mechanism of their action in AD remains unclear. Through sequencing of aortic clinical samples from AD patients, we identified piRNA-0228 (piR-0228) as the most significantly downregulated piRNA in AD patients compared with healthy populations. Overexpression and knockdown of piR-0228 in mouse monocyte macrophage leukemia cells (RAW264.7) and aortic vascular smooth muscle cells (VSMCs) revealed that piR-0228 regulates key cytopathic processes, primarily involving inflammatory response and necrosis, driven by stimulator of interferon genes (STING) pathway. Bioinformatics analysis and validation demonstrated that receptor-interacting protein kinase 1 (RIPK1) was a direct target gene of piR-0228, confirmed by both in vivo and in vitro studies. Finally, in an AD animal model, we observed that piR-0228 agomir significantly reduced mortality, morbidity, inflammation and vascular remodeling, demonstrating the effective therapy of piR-0228 agomir in reversing the disease's pathological progression. Therefore, our findings establish piR-0228 as a promising therapeutic target for AD and provide valuable insights for the future development of clinical treatment strategies for this condition.