Theranostics 2023; 13(2):531-542. doi:10.7150/thno.80289 This issue Cite

Research Paper

SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells

Nunzia D'Onofrio1*, Francesco Prattichizzo2*, Raffaele Marfella3,4, Celestino Sardu3, Elisa Martino1, Lucia Scisciola3, Lorenza Marfella3, Rosalba La Grotta2, Chiara Frigé2, Giuseppe Paolisso3,4, Antonio Ceriello2✉, Maria Luisa Balestrieri1✉

1. Department of Precision Medicine, the University of Campania “Luigi Vanvitelli” Italy.
2. IRCCS MultiMedica, Via Fantoli 16/15, 20138, Milan, Italy.
3. Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Luigi Miraglia 2, 80138, Naples, Italy.
4. Mediterranea Cardiocentro, 80122, Naples, Italy.
*These authors contributed equally to the manuscript.

Citation:
D'Onofrio N, Prattichizzo F, Marfella R, Sardu C, Martino E, Scisciola L, Marfella L, Grotta RL, Frigé C, Paolisso G, Ceriello A, Balestrieri ML. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics 2023; 13(2):531-542. doi:10.7150/thno.80289. https://www.thno.org/v13p0531.htm
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Abstract

Graphic abstract

Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (i) are a class of lipid-lowering drugs suggested to hold a plethora of beneficial effects independent of their LDL cholesterol-lowering properties. However, the mechanism underlying such observations is debated.

Methods: Human aortic endothelial cells (TeloHAEC) were pre-treated with 100 µg/mL of the PCSK9i evolocumab and then exposed to 20 ng/mL of IL-6, a major driver of cardiovascular diseases (CVD), in both naïve state and after siRNA-mediated suppression of the NAD-dependent deacetylase sirtuin-3 (SIRT3). Inflammation, autophagy, and oxidative stress were assessed through Western Blots, ELISAs, and/or immunofluorescence coupled by flow cytometry. To explore the human relevance of the findings, we also evaluated the expression of IL-6, SIRT3, IL-1β, the ratio LC3B II/I, and PCSK9 within the plaques of patients undergoing carotid endarterectomy (n=277), testing possible correlations between these proteins.

Results: PCSK9i improved a range of phenotypes including the activation of inflammatory pathways, oxidative stress, and autophagy. Indeed, treatment with PCSK9i was able to counteract the IL-6 induced increase in inflammasome activation, the accrual of autophagic cells, and mitochondrial ROS accumulation. Of note, silencing of SIRT3 reverted the beneficial effects observed with PCSK9i treatment on all these phenomena. In atheroma specimens, the expression of PCSK9 was inversely related to that of SIRT3 while positively correlating with IL-6, IL-1β, and the ratio LC3B II/I.

Conclusions: Overall, these data suggest that PCSK9i bear intrinsic anti-inflammatory, anti-autophagic, and antioxidant properties in endothelial cells, and that these pleiotropic effects might be mediated, at least in part, by SIRT3. These results provide an additional mechanism supporting the emerging knowledge relative to the benefit of PCSK9i on CVD beyond LDL-lowering and uncover SIRT3 as a putative mediator of such pleiotropy.

Keywords: PCSK9, SIRT3, IL-6, endothelial cells, cardiovascular diseases, ROS, oxidative stress, inflammation, autophagy, LDL-cholesterol, inflammasome


Citation styles

APA
D'Onofrio, N., Prattichizzo, F., Marfella, R., Sardu, C., Martino, E., Scisciola, L., Marfella, L., Grotta, R.L., Frigé, C., Paolisso, G., Ceriello, A., Balestrieri, M.L. (2023). SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics, 13(2), 531-542. https://doi.org/10.7150/thno.80289.

ACS
D'Onofrio, N.; Prattichizzo, F.; Marfella, R.; Sardu, C.; Martino, E.; Scisciola, L.; Marfella, L.; Grotta, R.L.; Frigé, C.; Paolisso, G.; Ceriello, A.; Balestrieri, M.L. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics 2023, 13 (2), 531-542. DOI: 10.7150/thno.80289.

NLM
D'Onofrio N, Prattichizzo F, Marfella R, Sardu C, Martino E, Scisciola L, Marfella L, Grotta RL, Frigé C, Paolisso G, Ceriello A, Balestrieri ML. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics 2023; 13(2):531-542. doi:10.7150/thno.80289. https://www.thno.org/v13p0531.htm

CSE
D'Onofrio N, Prattichizzo F, Marfella R, Sardu C, Martino E, Scisciola L, Marfella L, Grotta RL, Frigé C, Paolisso G, Ceriello A, Balestrieri ML. 2023. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. Theranostics. 13(2):531-542.

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