Key result
Endothelial RpL17 deficiency increases carotid intima-media thickening under disturbed flow by activating ER stress.
Decreased RpL17 in endothelial cells promotes intima-media thickening under disturbed flow via endoplasmic reticulum stress and altered translational control, highlighting a novel mechanism for cardiovascular pathology.
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Hypothesis-generating for endothelial RpL17 in flow-mediated remodeling; leaves open human relevance and requires prospective validation.
Background: Carotid intima-media thickening (IMT) is a major risk factor for cardiovascular disease (CVD). The large ribosomal subunit protein 17 (Rpl17) was recently reported as a CVD-associated gene; however, ribosomal mutations generally are not associated with vascular dysfunction. We have created a novel genetic model of decreased RpL17 in endothelial cells (EC) to determine how changes in endothelial ribosome expression cause IMT. Methods: were exposed to steady (s)-flow or d-flow using cone viscometry, and collected for flow cytometry, protein expression, electron microscopy, or purification of ribosomes. Human carotid samples from healthy and endarterectomy patients were used for tissue analysis. Results: Carotids from RpL17-Het mice with PCL-induced d-flow showed increased IMT relative to RpL17-WT controls. In addition, RpL17 protein levels were decreased in regions of d-flow compared to s-flow. Increased levels of ER stress markers were observed by carotid immunostaining, as well as activation of the integrated stress response (ISR) in RpL17-Het EC. Analysis of mRNAs bound to polysomes vs. monosomes in EC-RpL17-Het revealed increased translational efficiency of key regulators of glycolysis, redox, inflammation, matrix, and endothelial-to-mesenchymal transition (EndMT). Metabolic profiling by Seahorse assay showed enhanced anaerobic glycolysis and decreased oxidative respiration in RpL17-Het EC, consistent with the translational efficiency data. Immunostaining of carotids identified upregulated EC inflammation and EndMT. Conclusions: Our data support RpL17 as a key mediator of EC phenotypic modulation that causes IMT in response to d-flow. We show a novel pathway for d-flow-mediated IMT: endoplasmic reticulum stress and activation of the ISR. These changes alter translational efficiency and reprogram EC cell cycle, metabolism, and redox state in the presence of d-flow to cause IMT, a precursor to cardiovascular pathology.
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Wines-Samuelson et al. (2026) studied this question. Endothelial RpL17 deficiency increases carotid intima-media thickening in response to disturbed flow by activating endoplasmic reticulum stress and the integrated stress response.
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