Flow-Induced MicroRNA-210 Mediates Aortic Valve Pathogenesis via Coordinated Effects on Valvular Endothelial and Interstitial Cells

Z. Li (Bonn)¹, Y. Sheng (Bonn)², A. M. Utami (Bonn)³, J. I. Muñoz-Manco (Bonn)⁴, P. R. Goody (Bonn)⁵, K. Wilhelm-Jüngling (Bonn)⁶, N. Gerdes (Düsseldorf)⁷, S. Zimmer (Bonn)⁵, F. Bakhtiary (Bonn)⁸, G. Nickenig (Bonn)⁵, M. R. Hosen (Bonn)^4
1Heart Center Bonn, Molecular Cardiology, Department of Internal Medicine II Department of Internal Medicine II, University Hospital Bonn Bonn, Deutschland; ²Heart Center, Molecular Cardiology Med-II Bonn, Deutschland; ³Heart Center Bonn, Molecular Cardiology, Department of Internal Medicine II, University Hospital Bonn, Department of Internal Medicine II, University Hospital Bonn Bonn, Deutschland; ⁴Heart Center, Molecular Cardilogy Internal Medicine-II Bonn, Deutschland; ⁵Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; ⁶Institute for Cardiovascular Sciences Endothelial Signaling and Metabolism Bonn, Deutschland; ⁷Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; ⁸Universitätsklinikum Bonn Klinik und Poliklinik für Herzchirurgie Bonn, Deutschland

Background: Aortic valve stenosis (AVS) and coronary artery disease (CAD) are interconnected cardiovascular disorders driven by calcification and endothelial dysfunction. The mechano-sensitive miRNA miR-210 is upregulated by pathological flow, but its cell-specific roles in these diseases remain undefined. This study investigates how miR-210 contributes to endothelial-to-mesenchymal transition (EndMT) and valvular calcification in AVS and CAD.

Methods and Results: We systematically dissected miR-210's function in human coronary artery endothelial cells (HCAECs), coronary artery smooth muscle cells (HCASMCs), valvular endothelial cells (VECs), and valvular interstitial cells (VICs). siRNA-mediated knockdown of miR-210 was highly efficient (p<0.01). Under oxidative stress, miR-210 silencing in CAD-related cells enhanced HCAEC proliferation (p<0.05), reduced HCASMC cytotoxicity (p<0.05), and suppressed key inflammatory cytokines (IL-6, IL-1β, TNF-α; p<0.01). In AVS models, miR-210 knockdown in VECs impaired angiogenesis and migration. Crucially, under EndMT-inducing conditions, miR-210 suppression preserved the endothelial phenotype, inhibited mesenchymal transition, and upregulated VEGFA. Most strikingly, in VICs under pro-calcifying conditions, miR-210 knockdown potently inhibited calcification (p<0.01), while its overexpression exacerbated it, identifying miR-210 as a critical driver of osteogenesis.

Conclusion: Our data establish miR-210 as a central, cell-type-specific regulator promoting disease in both AVS and CAD, driving EndMT in endothelial cells and calcification in VICs. These findings nominate miR-210 as a promising diagnostic biomarker and therapeutic target. Future work will validate its direct targets in vivo and explore its translational potential.