Inhibition of RIPK1 alleviating vascular smooth muscle cells osteogenic transdifferentiation via Runx2

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Vascular Biology

Background:

• Vascular calcification (VC) is a significant risk factor for cardiovascular diseases.
• Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) contributes to VC, but molecular drivers are unclear.
• Receptor-interacting protein kinase 1 (RIPK1) is linked to cardiovascular diseases, but its role in VC is unknown.

Purpose of the Study:

• To investigate the role and molecular mechanisms of RIPK1 in vascular calcification.
• To determine if RIPK1 inhibition can prevent or reduce VC.

Main Methods:

• Utilized chronic kidney disease mouse models and in vitro VSMC calcification models.
• Assessed RIPK1 activation in human calcified arterial tissue, animal models, and cellular models.
• Administered a RIPK1-specific inhibitor (NEC-1) in both in vitro and in vivo settings.

Main Results:

• RIPK1 was significantly activated in calcified human arteries, animal models, and VSMCs.
• RIPK1 activation was found to promote the osteogenic transdifferentiation of VSMCs.
• Treatment with the RIPK1 inhibitor NEC-1 substantially reduced vascular calcification in both experimental models.

Conclusions:

• RIPK1 plays a critical role in promoting vascular calcification through VSMC osteogenic transdifferentiation.
• Targeting RIPK1 with inhibitors like NEC-1 presents a promising therapeutic strategy for preventing vascular calcification.