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Circulating micro-rna profiles according to atherosclerotic disease expression : a contribute to phenotype characterization and insights into pathophysiology / Tiago Luís Pinto Pereira da Silva ; orient. Miguel Mota Carmo... [et al.]

Main Author Silva, Tiago Luís Pinto Pereira da Secondary Author Carmo, Miguel Adriano Bento Mota Carmo
Napoleão, Patrícia
Filipe, Carlos
Publication Lisboa : NOVA Medical School, 2022 Abstract Background:Atherosclerosis involving multiple territories is frequently encountered in clinical practice and is associated with a higher morbidity and risk of mortality compared with a localized, single-territorial atherosclerosis. Multi-territorial atherosclerosis may have a different pathophysiology fromthat of single-territorial atherosclerosis, although little is known aboutthe mechanisms that regulate the atherosclerosis extent tosingle or multiple arterial beds. In fact, the heterogeneity in the systemic extent of atherosclerosis is only partially attributable to acquired cardiovascular risk factors and genetic Mendelian inheritance, and post-transcriptionalfactors (microRNAs) and inflammatorymediatorsmaycontribute independently to such heterogeneity. MicroRNAs are small non-coding molecules of ribonucleic acid that regulate the gene expression at the post-transcriptional leveland participate in different pathwaysassociated with atherogenesis and atherosclerotic disease expression. Regarding the inflammatory mediators, soluble CD40 ligand (sCD40L) and tumor necrosis factor alpha(TNF-α)are two proinflammatory and proatherogenic biomarkerswith distinct mechanismsof actionand bothareregulated in vitro by microRNAs. Knowledge on the signature of circulating microRNAs and inflammatory markers in single-and multi-territorial atherosclerosis may contribute to not only a better understanding of pathophysiology but also clinical care, since such mediators may potentially be used as diagnostic biomarkers and therapeutic targets.Aims:The main objectiveof this research project was to assess whether the expression of circulating microRNAs is associated with the systemic extent of atherosclerosis to a single (coronary) or multiple (coronary and extra-coronary) arterial territories.In addition, we assessed: whetherthe expression of circulating microRNAs is associated with the severity of atherosclerosis in different arterial territories; whether the expression of circulating microRNAs is associated with the presence ofcardiovascular risk factors, including cigarette smoking; whether the expression of inflammatory biomarkers, specifically sCD40L and TNF-α,is associated with the atherosclerosis extent to a single or multiple arterial territoriesand with the severity of atherosclerosis in different arterial territories; and whether thereis an association between the expression of circulating microRNAs andinflammatory biomarkersin patients with atherosclerosis. 2Methods:Participants wereprospectively recruited and divided into five age-and sex-matched groups: control, with no coronary, lower extremity (LE), or carotid atherosclerosis; group 1, with isolated coronary atherosclerosis; group 2, with coronary and LE atherosclerosis; group 3, with coronary and carotid atherosclerosis; and group 4, with atherosclerosis of the coronary, LE, and carotid territories.Native obstructive atherosclerosis was the defining criterion for the presence of disease in each territory and group assignment. All the participants were screened for atherosclerotic disease in the three territories. The relative expression levels of six candidate microRNAs(miR-21, miR-27b, miR-29a, miR-126, miR-146a, and miR-218)wereassessed. The selection criteria of candidate microRNAs werethe distinct biological roles inatherosclerosis regulation, based on experimental studies,and their reported dysregulation in patients with single-territorialatherosclerosis.Serum levels of sCD40L and TNF-αwere assessed by an enzyme-linked immunosorbent assay.Results:A total of 94 participants were included: 26 control participants, 20 with isolated coronary atherosclerosis (group 1), 18 with coronary and LE atherosclerosis (group 2), 12 with coronary and carotid atherosclerosis (group 3), and 18 with atherosclerosis of the coronary, LE, and carotid territories(group 4). The clinical, demographic, and laboratory data and parameters of coronary atherosclerosis severity were well-balanced among groups 1 to 4. Lower expression levels of miR-27b and miR-146awere associated with the presence of multi-territorial atherosclerosis, particularly if involving the coronary, LE, and carotid territories,and with higherseverity of atherosclerosisin the threeterritories. The coexistence of atherosclerosis in the three territories was independently associated with the miR-27b and miR-146aexpression levels and both microRNAs presented an area under the receiver operating characteristics curve ≥ 0.75 to predictatherosclerosis of the three territories.Regarding the association between microRNAs expression and cardiovascular risk factors, multivariate modelsindicated thatcigarette smoking was associated with the presence of LE atherosclerosis, cigarette smoking was associated with miR-27b downregulation, and miR-27b downregulation was associated with the presence of LE atherosclerosis.Active smokers, but not prior smokers,presented a downregulation of miR-27b.Regarding the expression of inflammatory biomarkers, higher sCD40L levels were associated withan increased systemic extent of atherosclerosis to multiple territories, specifically the coronary and LE territories, and increased severity of atherosclerosis in thoseterritories. Priorsurgicalrevascularization of the coronary and/or LEarteries was associated with lower sCD40L levels.RegardingTNF-α, metabolic and post-transcriptional (miR-146a) factorswere 3associated with TNF-αlevelsin patients with coronary atherosclerosis. miR-146aexpression levels were negatively correlated with TNF-αlevelsand thisassociation was independent of other metabolic and inflammatory parameters.Conclusions: Theexpression levels of miR-27b and miR-146awere associated with the presence of multi-territorial atherosclerosis, particularly if involving the coronary, LE, and carotid territories,and with the severity of atherosclerosis in the threeterritories. Both microRNAs showed reasonable accuracy for predicting multi-territorial atherosclerosisinvolving the coronary, LE, and carotid territories. Of these microRNAs, miR-27b appeared to be a mediator of cigarette smoking-induced toxicity, specifically LE atherosclerosis. The sCD40L levels were associated with the systemic extent of atherosclerosis to multiple territories, particularly the coronary and LE territories,and atherosclerosis severity in thoseterritories, showingalsoa distinct expression according to prior arterial revascularization. Finally, TNF-αlevels were inverselycorrelated with miR-146aexpression levels. These dataprovide a post-transcriptional (microRNA) and inflammatory signature of multi-territorial atherosclerosis and point to the relevance of such mediators in the regulation of the systemic extent of atherosclerosis. Moreover, miR-27b and miR-146aare promising noninvasive biomarkers for refining the stratification of systemic atherosclerotic burden, and likely it also applies to sCD40L. These biomarkers may therefore contribute to the tailoring of primary prevention strategies. Topical name Atherosclerosis
MicroRNAs
miR-27b
miR-146a
multi-territorialdisease
soluble CD40 ligand
Tumor necrosis factor alpha
Academic Dissertations
Portugal
Index terms Tese de Doutoramento
Medicina Investigação Clínica
Universidade NOVA de Lisboa
NOVA Medical School
2022
Online Resources Click here to access the eletronic resource http://hdl.handle.net/10362/134274
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RUN http://hdl.handle.net/10362/134274 Available 20220050

Background:Atherosclerosis involving multiple territories is frequently encountered in clinical practice and is associated with a higher morbidity and risk of mortality compared with a localized, single-territorial atherosclerosis. Multi-territorial atherosclerosis may have a different pathophysiology fromthat of single-territorial atherosclerosis, although little is known aboutthe mechanisms that regulate the atherosclerosis extent tosingle or multiple arterial beds. In fact, the heterogeneity in the systemic extent of atherosclerosis is only partially attributable to acquired cardiovascular risk factors and genetic Mendelian inheritance, and post-transcriptionalfactors (microRNAs) and inflammatorymediatorsmaycontribute independently to such heterogeneity. MicroRNAs are small non-coding molecules of ribonucleic acid that regulate the gene expression at the post-transcriptional leveland participate in different pathwaysassociated with atherogenesis and atherosclerotic disease expression. Regarding the inflammatory mediators, soluble CD40 ligand (sCD40L) and tumor necrosis factor alpha(TNF-α)are two proinflammatory and proatherogenic biomarkerswith distinct mechanismsof actionand bothareregulated in vitro by microRNAs. Knowledge on the signature of circulating microRNAs and inflammatory markers in single-and multi-territorial atherosclerosis may contribute to not only a better understanding of pathophysiology but also clinical care, since such mediators may potentially be used as diagnostic biomarkers and therapeutic targets.Aims:The main objectiveof this research project was to assess whether the expression of circulating microRNAs is associated with the systemic extent of atherosclerosis to a single (coronary) or multiple (coronary and extra-coronary) arterial territories.In addition, we assessed: whetherthe expression of circulating microRNAs is associated with the severity of atherosclerosis in different arterial territories; whether the expression of circulating microRNAs is associated with the presence ofcardiovascular risk factors, including cigarette smoking; whether the expression of inflammatory biomarkers, specifically sCD40L and TNF-α,is associated with the atherosclerosis extent to a single or multiple arterial territoriesand with the severity of atherosclerosis in different arterial territories; and whether thereis an association between the expression of circulating microRNAs andinflammatory biomarkersin patients with atherosclerosis. 2Methods:Participants wereprospectively recruited and divided into five age-and sex-matched groups: control, with no coronary, lower extremity (LE), or carotid atherosclerosis; group 1, with isolated coronary atherosclerosis; group 2, with coronary and LE atherosclerosis; group 3, with coronary and carotid atherosclerosis; and group 4, with atherosclerosis of the coronary, LE, and carotid territories.Native obstructive atherosclerosis was the defining criterion for the presence of disease in each territory and group assignment. All the participants were screened for atherosclerotic disease in the three territories. The relative expression levels of six candidate microRNAs(miR-21, miR-27b, miR-29a, miR-126, miR-146a, and miR-218)wereassessed. The selection criteria of candidate microRNAs werethe distinct biological roles inatherosclerosis regulation, based on experimental studies,and their reported dysregulation in patients with single-territorialatherosclerosis.Serum levels of sCD40L and TNF-αwere assessed by an enzyme-linked immunosorbent assay.Results:A total of 94 participants were included: 26 control participants, 20 with isolated coronary atherosclerosis (group 1), 18 with coronary and LE atherosclerosis (group 2), 12 with coronary and carotid atherosclerosis (group 3), and 18 with atherosclerosis of the coronary, LE, and carotid territories(group 4). The clinical, demographic, and laboratory data and parameters of coronary atherosclerosis severity were well-balanced among groups 1 to 4. Lower expression levels of miR-27b and miR-146awere associated with the presence of multi-territorial atherosclerosis, particularly if involving the coronary, LE, and carotid territories,and with higherseverity of atherosclerosisin the threeterritories. The coexistence of atherosclerosis in the three territories was independently associated with the miR-27b and miR-146aexpression levels and both microRNAs presented an area under the receiver operating characteristics curve ≥ 0.75 to predictatherosclerosis of the three territories.Regarding the association between microRNAs expression and cardiovascular risk factors, multivariate modelsindicated thatcigarette smoking was associated with the presence of LE atherosclerosis, cigarette smoking was associated with miR-27b downregulation, and miR-27b downregulation was associated with the presence of LE atherosclerosis.Active smokers, but not prior smokers,presented a downregulation of miR-27b.Regarding the expression of inflammatory biomarkers, higher sCD40L levels were associated withan increased systemic extent of atherosclerosis to multiple territories, specifically the coronary and LE territories, and increased severity of atherosclerosis in thoseterritories. Priorsurgicalrevascularization of the coronary and/or LEarteries was associated with lower sCD40L levels.RegardingTNF-α, metabolic and post-transcriptional (miR-146a) factorswere 3associated with TNF-αlevelsin patients with coronary atherosclerosis. miR-146aexpression levels were negatively correlated with TNF-αlevelsand thisassociation was independent of other metabolic and inflammatory parameters.Conclusions: Theexpression levels of miR-27b and miR-146awere associated with the presence of multi-territorial atherosclerosis, particularly if involving the coronary, LE, and carotid territories,and with the severity of atherosclerosis in the threeterritories. Both microRNAs showed reasonable accuracy for predicting multi-territorial atherosclerosisinvolving the coronary, LE, and carotid territories. Of these microRNAs, miR-27b appeared to be a mediator of cigarette smoking-induced toxicity, specifically LE atherosclerosis. The sCD40L levels were associated with the systemic extent of atherosclerosis to multiple territories, particularly the coronary and LE territories,and atherosclerosis severity in thoseterritories, showingalsoa distinct expression according to prior arterial revascularization. Finally, TNF-αlevels were inverselycorrelated with miR-146aexpression levels. These dataprovide a post-transcriptional (microRNA) and inflammatory signature of multi-territorial atherosclerosis and point to the relevance of such mediators in the regulation of the systemic extent of atherosclerosis. Moreover, miR-27b and miR-146aare promising noninvasive biomarkers for refining the stratification of systemic atherosclerotic burden, and likely it also applies to sCD40L. These biomarkers may therefore contribute to the tailoring of primary prevention strategies.

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