SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells
Source : https://www.thno.org/v13p0531.htm
Theranostics 2023; 13(2):531-542. doi:10.7150/thno.80289 This issue Cite Research Paper Nunzia D'Onofrio 1*, Francesco Prattichizzo 2*, Raffaele Marfella 3,4, Celestino Sardu 3, Elisa Martino 1, Lucia Scisciola 3, Lorenza Marfella 3, Rosalba La Grotta 2, Chiara Frigé 2, Giuseppe Paolisso 3,4, Antonio Ceriello 2 , Maria Luisa Balestrieri 1 1.
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.
• Source: Theranostics
• 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.”
• First, the Italian researchers assessed the potential for PCSK9 inhibitors to countervail the pro-inflammatory, pro-oxidant, and pro-autophagic effects of IL-6 in endothelial cells. Second, the assessed the role of SIRT3 in blunting these phenomena. Third, they assessed the association between IL-6 and the expression of SIRT3, IL-1β, the ratio LC3B II/I, and PCSK9 in plaques of patients receiving carotid endarterectomy.
• In addition to lowering LDL cholesterol levels, PCSK9 inhibitors exert positive, independent effects on EC, per the authors. “Here we substantiate these observations by showing that PCSK9i exert anti-inflammatory, anti-autophagic, and antioxidant effects in EC exposed to IL-6, a potent cytokine linked to the development of CVD. In our model, these beneficial effects were mediated, at least in part, by SIRT3, which downregulation largely blunted the protection conferred by PCSK9i.”
• The authors observed a negative correlation between the expression of PCSK9 protein and SIRT3 within patient plaques. On the other hand, IL-6, IL-1β, and the ratio LC3B II/I was positively associated with PCSK9 and negatively correlated with SIRT3. These findings support a process where PCSK9 inhibitors could diminish a pathological cascade triggered via low-grade inflammation.
• This study is the first to suggest a framework displaying a role for SIRT3 in the cardioprotective effects advanced by PCSK9i.
• Limitations of the study include the investigators not exploring whether the modulation of autophagy is beneficial or detrimental for EC function. They also did not evaluate whether plaque specimens from patients treated with a PCSK9 inhibitors exhibit a decreased burden of inflammation, autophagy, and oxidative stress vs. patients treated with alternative lipid-lowering drugs.