Nano-Polyplexes Mediated Transfection of Runx2-shRNA Mitigates the Osteodifferentiation of Human Valvular Interstitial Cells.
Geanina VoicuDaniela RebleanuCristina Ana ConstantinescuElena Valeria FuiorLetitia CiortanIonel DrocCristina Mariana UrituMariana PintealaIleana ManduteanuMaya SimionescuManuela CalinPublished in: Pharmaceutics (2020)
Calcific aortic valve disease (CAVD) is a progressive disorder that increases in prevalence with age. An important role in aortic valve calcification is played by valvular interstitial cells (VIC), that with age or in pathological conditions acquire an osteoblast-like phenotype that advances the disease. Therefore, pharmacological interventions aiming to stop or reverse the osteoblastic transition of VIC may represent a therapeutic option for CAVD. In this study, we aimed at developing a nanotherapeutic strategy able to prevent the phenotypic switch of human aortic VIC into osteoblast-like cells. We hypothesize that nanocarriers designed for silencing the Runt-related transcription factor 2 (Runx2) will stop the progress or reverse the osteodifferentiation of human VIC, induced by high glucose concentrations and pro-osteogenic factors. We report here the potential of fullerene (C60)-polyethyleneimine (PEI)/short hairpin (sh)RNA-Runx2 nano-polyplexes to efficiently down-regulate Runx2 mRNA and protein expression leading subsequently to a significant reduction in the expression of osteogenic proteins (i.e. ALP, BSP, OSP and BMP4) in osteoblast-committed VIC. The data suggest that the silencing of Runx2 could represent a novel strategy to impede the osteoblastic phenotypic shift of VIC and the ensuing progress of CAVD.
Keyphrases
- aortic valve
- transcription factor
- endothelial cells
- transcatheter aortic valve replacement
- aortic valve replacement
- transcatheter aortic valve implantation
- aortic stenosis
- high glucose
- induced apoptosis
- mesenchymal stem cells
- induced pluripotent stem cells
- cell cycle arrest
- dna binding
- bone marrow
- bone regeneration
- pluripotent stem cells
- atrial fibrillation
- poor prognosis
- physical activity
- heart failure
- coronary artery
- endoplasmic reticulum stress
- risk factors
- signaling pathway
- pulmonary artery
- binding protein
- risk assessment
- machine learning
- radiation therapy
- artificial intelligence
- coronary artery disease
- drug release
- left ventricular
- oxidative stress
- pulmonary hypertension