Endothelial cell RpL17-dependent translational control mediates intima-media thickening in response to disturbed flow

Area of Science:

• Vascular Biology
• Cardiovascular Research
• Molecular Medicine

Background:

• Carotid intima-media thickening (IMT) is a significant risk factor for cardiovascular disease (CVD).
• Large ribosomal subunit protein 17 (Rpl17) has been implicated in CVD, but its role in vascular dysfunction is unclear.
• Ribosomal protein alterations are not typically associated with vascular pathologies.

Purpose of the Study:

• To investigate the role of endothelial cell (EC)-specific Rpl17 reduction in the development of IMT.
• To elucidate the molecular mechanisms by which altered endothelial ribosome expression contributes to IMT.
• To establish a novel genetic model for studying endothelial dysfunction and IMT.

Main Methods:

• Generated EC-restricted Rpl17 heterozygous mice (Rpl17-Het) for studying IMT.
• Utilized partial carotid ligation (PCL) to induce disturbed (d)-flow and assessed IMT.
• Analyzed ECs in vitro under steady (s)-flow and d-flow conditions using flow cytometry, protein analysis, and ribosome profiling.
• Examined human carotid endarterectomy samples for Rpl17 expression and related markers.

Main Results:

• Rpl17-Het mice subjected to PCL exhibited increased IMT compared to controls.
• Decreased Rpl17 protein levels were observed in regions of d-flow.
• ECs from Rpl17-Het mice showed increased ER stress, ISR activation, and altered translational efficiency of key metabolic and inflammatory genes.
• Enhanced glycolysis and EndMT were observed in Rpl17-Het ECs under d-flow.

Conclusions:

• Rpl17 is a critical mediator of EC phenotypic modulation leading to IMT in response to d-flow.
• A novel pathway involving ER stress and ISR activation mediates d-flow-induced IMT.
• Altered translational efficiency and cellular reprogramming in ECs contribute to IMT, a precursor to cardiovascular pathology.