Identification of DKK-1 as a novel mediator of statin effects in human endothelial cells

Pontremoli, Marta; Brioschi, Maura; Baetta, Roberta; Ghilardi, Stefania; Banfi, Cristina

doi:10.1038/s41598-018-35119-7

Cited by 33 publications

(22 citation statements)

References 70 publications

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“…Furthermore, Pontremoli et al have speculated that the DKK-1 pathway might be influenced by statin treatment. The concentration of these proteins, members of the Dickkopf family, would be decreased after statin administration, resulting in diminished platelet recruitment and activity [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Effect of Statins on Platelet Activation and Function: From Molecular Pathways to Clinical Effects

Nenna

Nappi

Lusini

et al. 2021

BioMed Research International

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Purpose. Statins are a class of drugs widely used in clinical practice for their lipid-lowering and pleiotropic effects. In recent years, a correlation between statins and platelet function has been unveiled in the literature that might introduce new therapeutic indications for this class of drugs. This review is aimed at summarizing the mechanisms underlying statin-platelet interaction in the cardiologic scenario and building the basis for future in-depth studies. Methods. We conducted a literature search through PubMed, Embase, EBSCO, Cochrane Database of Systematic Reviews, and Web of Science from their inception to June 2020. Results. Many pathways could explain the interaction between statins and platelets, but the specific effect depends on the specific compound. Some could be mediated by enzymes that allow the entry of drugs into the cell (OATP2B1) and others by enzymes that mediate their activation (PLA2, MAPK, TAX2, PPARs, AKT, and COX-1), recruitment and adhesion (LOX-1, CD36, and CD40L), or apoptosis (BCL2). Statins also appear to have a synergistic effect with aspirin and low molecular weight heparins. Surprisingly, they seem to have an antagonistic effect with clopidogrel. Conclusion. There are many pathways potentially responsible for the interactions between statins and platelets. Their effect appears to be closely related, and each single effect can be barely measured. Also, the same compound might have complex downstream signaling with potentially opposite effects, i.e., beneficial or deleterious. The multiple clinical implications that can be derived as a result of this interaction, however, represent an excellent reason to develop future in-depth studies.

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Section: Resultsmentioning

confidence: 99%

Effect of Statins on Platelet Activation and Function: From Molecular Pathways to Clinical Effects

Nenna

Nappi

Lusini

et al. 2021

BioMed Research International

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“…Data were analyzed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING 11.0) database [ 28 ] as previously described [ 29 ] to identify enriched Gene Ontology (GO) terms in the biological process, molecular function, or cellular component categories. We specifically employed the enrichment widget of STRING, which calculates an enrichment p value based on the hypergeometric test and the method of Benjamini and Hochberg for correction of multiple testing ( p value cutoff of < 0.05).…”

Section: Methodsmentioning

confidence: 99%

Sex-dependent differences in the secretome of human endothelial cells

et al. 2021

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Background Cellular sex has rarely been considered as a biological variable in preclinical research, even when the pathogenesis of diseases with predictable sex differences is studied. In this perspective, proteomics, and “omics” approaches in general, can provide powerful tools to obtain comprehensive cellular maps, thus favoring the discovery of still unknown sex-biased physio-pathological mechanisms. Methods We performed proteomic and Gene Ontology (GO) analyses of the secretome from human serum-deprived male and female endothelial cells (ECs) followed by ELISA validation. Apoptosis was detected by FACS and Western blot techniques and efferocytosis through the ability of the macrophage cell line RAW 264.7 to engulf apoptotic ECs. PTX3 mRNA levels were measured by RT-qPCR. Results Proteomic and GO analyses of the secretome from starved human male and female ECs demonstrated a significant enrichment in proteins related to cellular responses to stress and to the regulation of apoptosis in the secretome of male ECs. Accordingly, a higher percentage of male ECs underwent apoptosis in response to serum deprivation in comparison with female ECs. Among the secreted proteins, we reliably found higher levels of PTX3 in the male EC secretome. The silencing of PTX3 suggested that male ECs were dependent on its expression to properly carry out the efferocytotic process. At variance, female EC efferocytosis seemed to be independent on PTX3 expression. Conclusions Our results demonstrated that serum-starved male and female ECs possess different secretory phenotypes that might take part in the sex-biased response to cellular stress. We identified PTX3 as a crucial player in the male-specific endothelial response to an apoptotic trigger. This novel and sex-related role for secreted proteins, and mainly for PTX3, may open the way to the discovery of still unknown sex-specific mechanisms and pharmacological targets for the prevention and treatment of endothelial dysfunction at the onset of atherosclerosis and cardiovascular disease.

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“…Data were analyzed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING 11.0) database [28] as previously described [29] to identify enriched gene ontology (GO) terms in the biological process, molecular function or cellular component categories. We speci cally employed the enrichment widget of STRING, which calculates an enrichment P-value based on the Hypergeometric test and the method of Benjamini and Hochberg for correction of multiple testing (P value cut-off of <0.05).…”

Section: Gene Ontology Analysismentioning

confidence: 99%

Sex-dependent differences in the secretome of human endothelial cells

Cattaneo

Banfi

Brioschi

et al. 2020

Preprint

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Background: Cellular sex has been rarely considered as a biological variable in preclinical research, even when the pathogenesis of diseases with predictable sex differences is studied. In this perspective, proteomics, and ‘omics approaches in general, can provide powerful tools to obtain comprehensive cellular maps, thus favoring the discovery of still unknown sex-biased physio-pathological mechanisms.Methods: We performed proteomic and gene ontology (GO) analyses of secretome from human serum-deprived male and female endothelial cells (ECs) followed by ELISA validation. Apoptosis was detected by FACS and western blot techniques, and efferocytosis through the ability of the macrophage cell line RAW-264.7 to engulf apoptotic ECs. PTX3 mRNA levels were measured by RT-qPCR. Results: Proteomic and GO analyses of the secretome from starved human male and female ECs demonstrated a significant enrichment in proteins related to cellular responses to stress and to the regulation of apoptosis in the secretome of male ECs. Accordingly, a higher percentage of male ECs underwent apoptosis in response to serum deprivation in comparison to female ECs. Among the secreted proteins, we reliably found higher levels of PTX3 in the male EC secretome. The silencing of PTX3 suggests that male ECs were dependent on its expression to properly carry out the efferocytotic process. At variance, female EC efferocytosis seems to be independent on PTX3 expression. Conclusions: Our results demonstrated that serum-starved male and female ECs possess different secretory phenotypes that might take part in the sex-biased response to cellular stress. We identified PTX3 as a crucial player in the male-specific endothelial response to an apoptotic trigger. This novel and sex-related role for secreted proteins, and mainly for PTX3, may open the way to the discovery of still unknown sex-specific mechanisms and pharmacological targets for the prevention and treatment of endothelial dysfunction at the onset of atherosclerosis and cardiovascular disease.

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Identification of DKK-1 as a novel mediator of statin effects in human endothelial cells

Cited by 33 publications

References 70 publications

Effect of Statins on Platelet Activation and Function: From Molecular Pathways to Clinical Effects

Effect of Statins on Platelet Activation and Function: From Molecular Pathways to Clinical Effects

Sex-dependent differences in the secretome of human endothelial cells

Sex-dependent differences in the secretome of human endothelial cells

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