Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

Rheumatoid Arthritis (RA), Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are the systemic autoimmune diseases (SADs) most associated with an increased risk of developing cardiovascular (CV) events. Cardiovascular disease (CVD) in SADs results from a complex interaction between traditional CV-risk factors, immune deregulation and disease activity. Oxidative stress, dyslipidemia, endothelial dysfunction, inflammatory/prothrombotic mediators (cytokines/chemokines, adipokines, proteases, adhesion-receptors, NETosis-derived-products, and intracellular-signaling molecules) have been implicated in these vascular pathologies. Genetic and genomic analyses further allowed the identification of signatures explaining the pro-atherothrombotic profiles in RA, SLE and APS. However, gene modulation has left significant gaps in our understanding of CV co-morbidities in SADs. MicroRNAs (miRNAs) are emerging as key post-transcriptional regulators of a suite of signaling pathways and pathophysiological effects. Abnormalities in high number of miRNA and their associated functions have been described in several SADs, suggesting their involvement in the development of atherosclerosis and thrombosis in the setting of RA, SLE and APS. This review focusses on recent insights into the potential role of miRNAs both, as clinical biomarkers of atherosclerosis and thrombosis in SADs, and as therapeutic targets in the regulation of the most influential processes that govern those disorders, highlighting the potential diagnostic and therapeutic properties of miRNAs in the management of CVD.

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Primary prevention of cardiovascular disease in patients with systemic lupus erythematosus: case series and literature review

Lupus ◽

10.1177/0961203317722847 ◽

2017 ◽

Vol 26 (14) ◽

pp. 1463-1472 ◽

Cited By ~ 15

Author(s):

S Fasano ◽

D P Margiotta ◽

L Navarini ◽

L Pierro ◽

I Pantano ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Cardiovascular Event ◽

Lupus Erythematosus ◽

Cardiovascular Events ◽

Hazard Ratio ◽

Systemic Lupus ◽

Increased Risk

Background Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a prophylactic role of cardiovascular events. This study is devoted to reviewing the literature on the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a two-centre Italian series. Methods A PubMed search on cardiovascular prevention in systemic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients admitted to two centres from 2000–2015, who at admission had not experienced any cardiovascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occurrence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox regression analyses were performed to evaluate the role of traditional, disease-related cardiovascular risk factors and of each of the three drugs in the occurrence of new cardiovascular events. Results The literature search produced conflicting results. Two hundred and ninety-one systemic lupus erythematosus patients were included in the study and followed for a median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years (hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32) increased, the risk of a first cardiovascular event. No effect of statins emerged. Conclusion Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophylaxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack of any detected effect in previous reports may depend on the design of studies and their short follow-up period.

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Regulatory Role of Sex Hormones in Cardiovascular Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms22094620 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4620

Author(s):

Holly J. Woodward ◽

Dongxing Zhu ◽

Patrick W. F. Hadoke ◽

Victoria E. MacRae

Keyword(s):

Cardiovascular Disease ◽

Sex Differences ◽

Sexual Dimorphism ◽

Aortic Stenosis ◽

Sex Hormones ◽

Sex Hormone ◽

Increased Risk ◽

Male Sex ◽

Primary Male

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.

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Intracellular signaling molecules of nerve tissue progenitors as pharmacological targets for treatment of ethanol-induced neurodegeneration

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0317 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Gleb Nikolaevich Zyuz’kov ◽

Larisa Arkad`evna Miroshnichenko ◽

Elena Vladislavovna Simanina ◽

Larisa Alexandrovna Stavrova ◽

Tatyana Yur`evna Polykova

Keyword(s):

Stem Cells ◽

Alcohol Abuse ◽

Intracellular Signaling ◽

Signaling Molecules ◽

Growth Potential ◽

Nerve Tissue ◽

Intracellular Signaling Molecules

Abstract Objectives The development of approaches to the treatment of neurodegenerative diseases caused by alcohol abuse by targeted pharmacological regulation of intracellular signaling transduction of progenitor cells of nerve tissue is promising. We studied peculiarities of participation of NF-кB-, сАМР/РКА-, JAKs/STAT3-, ERK1/2-, p38-pathways in the regulation of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in the simulation of ethanol-induced neurodegeneration in vitro and in vivo. Methods In vitro, the role of signaling molecules (NF-кB, сАМР, РКА, JAKs, STAT3, ERK1/2, p38) in realizing the growth potential of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in ethanol-induced neurodegeneration modeled in vitro and in vivo was studied. To do this, the method of the pharmacological blockade with the use of selective inhibitors of individual signaling molecules was used. Results Several of fundamental differences in the role of certain intracellular signaling molecules (SM) in proliferation and specialization of NSC and NCP have been revealed. It has been shown that the effect of ethanol on progenitors is accompanied by the formation of a qualitatively new pattern of signaling pathways. Data have been obtained on the possibility of stimulation of nerve tissue regeneration in ethanol-induced neurodegeneration by NF-кB and STAT3 inhibitors. It has been found that the blockage of these SM stimulates NSC and NCP in conditions of ethanol intoxication and does not have a «negative» effect on the realization of the growth potential of intact progenitors (which will appear de novo during therapy). Conclusions The results may serve as a basis for the development of fundamentally new drugs to the treatment of alcoholic encephalopathy and other diseases of the central nervous system associated with alcohol abuse.

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Peroxiredoxins as Potential Targets for Cardiovascular Disease

Antioxidants ◽

10.3390/antiox10081244 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1244

Author(s):

Se-Jin Jeong ◽

Jong-Gil Park ◽

Goo Taeg Oh

Keyword(s):

Cardiovascular Disease ◽

Intracellular Signaling ◽

Toxic Substance ◽

Regulatory Proteins ◽

The Past ◽

Glutathione Peroxidases ◽

Intracellular Signals ◽

Common Etiology ◽

Cardiovascular Cells

Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced by ROS. Hydrogen peroxide (H2O2), as an endogenous ROS in aerobic cells, is a toxic substance that can induce OS. However, many studies conducted over the past two decades have provided substantial evidence that H2O2 acts as a diffusible intracellular signaling messenger. Antioxidant enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), maintain the balance of ROS levels against augmentation of ROS production during the pathogenesis of CVD. Especially, Prdxs are regulatory sensors of transduced intracellular signals. The intracellular abundance of Prdxs that specifically react with H2O2 act as regulatory proteins. In this review, we focus on the role of Prdxs in the regulation of ROS-induced pathological changes in the development of CVD.

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Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial

Clinical Chemistry ◽

10.1373/clinchem.2015.251710 ◽

2016 ◽

Vol 62 (4) ◽

pp. 582-592 ◽

Cited By ~ 91

Author(s):

Miguel Ruiz-Canela ◽

Estefania Toledo ◽

Clary B Clish ◽

Adela Hruby ◽

Liming Liang ◽

...

Keyword(s):

Cardiovascular Disease ◽

Amino Acids ◽

Cardiovascular Death ◽

Branched Chain Amino Acids ◽

Control Group ◽

Cvd Risk ◽

Hazard Ratios ◽

Increased Risk ◽

Branched Chain

Abstract BACKGROUND The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05–2.76) and 2.09 (1.27–3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

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Association between Risk Factors for Vascular Dementia and Adiponectin

BioMed Research International ◽

10.1155/2014/261672 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 17

Author(s):

Juhyun Song ◽

Won Taek Lee ◽

Kyung Ah Park ◽

Jong Eun Lee

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Signal Transduction ◽

Vascular Dementia ◽

Case Control ◽

Case Control Studies ◽

Insulin Signal Transduction ◽

Increased Risk ◽

The Brain

Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia.

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The Role of Fetuin-A in Disease Processes Prevalent in Postmenopausal Women (El papel de la fetuina A en los procesos de enfermedad prevalentes en mujeres posmenopáusicas)

Retos ◽

10.47197/retos.v0i27.34372 ◽

2015 ◽

pp. 172-179

Author(s):

Annie A. Bane ◽

Peter W. Grandjean

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Postmenopausal Women ◽

Abdominal Fat ◽

Mineral Density ◽

Fetuin A ◽

Increased Risk ◽

Resistencia A La Insulina ◽

Low Levels

The purpose of this review is to summarize the role of fetuin-A in disease processes prevalent in postmenopausal women and synthesize effective interventions in obtaining healthy fetuin-A levels. A review of databases for articles related to fetuin-A and diseases associated with postmenopausal women was conducted. Articles were limited to full-text access, published in English since 1944. High fetuin-A levels are closely associated with decreased bone mineral density, increased cardiovascular disease risks, impairment of insulin signaling and disruption of adipocyte functioning. Postmenopausal women have increased risk of osteoporosis, cardiovascular disease, insulin-resistance, intra-abdominal fat accumulation and vascular calcification. Low-levels of fetuin-A have been shown to be protective against the latter. The role of fetuin-A is multi-factorial and the mechanisms in which it is involved in each of these processes are vast. The present body of literature is inconsistent in defining high versus low levels of fetuin-A and their association with healthy-matched controls. The diseases associated with high levels of fetuin-A mimic diseases most prevalent in postmenopausal women. In addition, there is no research, to date, exploring fetuin-A levels in postmenopausal women and the associations it may or may not have in related diseases.Key words: fetuin-A; Alpha2-Heremans-Schmid glycoprotein; cardiovascular disease; and elderly, insulin-resistance, intra-abdominal fat, metabolic syndrome, exercise, weight-loss, calorie restriction and postmenopausal.Resumen. El propósito de esta revisión es sintetizar el papel de la fetuina A en los procesos de enfermedad prevalentes en mujeres posmenopáusicas y resumir las intervenciones efectivas que permiten obtener niveles saludables de fetuina A. Para ello, se revisaron bases de datos con artículos relacionados con fetuina A y las enfermedades asociadas con mujeres posmenopáusicas. La búsqueda de artículos se limitó a aquellos de texto completo publicados en el idioma inglés desde el año 1944. Se encontró que altos niveles de fetuina A están íntimamente relacionados con una reducción de la densidad mineral ósea, un aumento en el riesgo de enfermedad cardiovascular, deterioro de la señalización de la insulina y la alteración del funcionamiento de los adipocitos. Las mujeres posmenopáusicas tienen un mayor riesgo de osteoporosis, enfermedad cardiovascular, resistencia a la insulina, acumulación de grasa intra abdominal y calcificación vascular. Se ha demostrado que niveles bajos de fetuina A son protectores contra esta última condición. El papel de fetuina A es multifactorial y los mecanismos en los que está involucrado en cada uno de estos procesos son muy amplios. El estado actual de la literatura no es consistente en la definición de niveles de fetuina A altos versus bajos y su asociación con controles sanos. Las enfermedades asociadas con altos niveles de fetuina A asemejan las enfermedades más prevalentes en mujeres posmenopáusicas. Además, no existen investigaciones, hasta la fecha, en las que se exploren los niveles de fetuina A en mujeres posmenopáusicas y las asociaciones que puede o no puede tener en las enfermedades relacionadas.Palabras claves: fetuina A, glicoproteína Alpha2-Heremans-Schmid, enfermedad cardiovascular, adulto mayor, resistencia a la insulina, grasa intra abdominal, síndrome metabólico, ejercicio, pérdida de peso, restricción calórica, posmenopausia.

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Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-212614 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1063-1069 ◽

Cited By ~ 8

Author(s):

Dag Leonard ◽

Elisabet Svenungsson ◽

Johanna Dahlqvist ◽

Andrei Alexsson ◽

Lisbeth Ärlestig ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

General Population ◽

Lupus Erythematosus ◽

Risk Allele ◽

Snp Array ◽

Inflammatory Rheumatic Diseases ◽

Systemic Lupus ◽

Increased Risk

ObjectivesPatients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.MethodsPatients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).ResultsWe identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.ConclusionsThe IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

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Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa258 ◽

2020 ◽

Author(s):

Preetika Sinh ◽

Raymond Cross

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Inflammatory Bowel Disease ◽

Cardiovascular Risk ◽

Lupus Erythematosus ◽

Bowel Disease ◽

Severe Heart Failure ◽

Janus Kinase ◽

Increased Risk ◽

Inflammatory Bowel

Abstract There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.

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Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients

International Journal of Molecular Sciences ◽

10.3390/ijms20092154 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2154 ◽

Cited By ~ 6

Author(s):

Mercurio ◽

Lobasso ◽

Barbieri ◽

Parrella ◽

Ciervo ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Arterial Stiffness ◽

Pulse Pressure ◽

Lupus Erythematosus ◽

Applanation Tonometry ◽

Main Role ◽

Systemic Lupus ◽

Markers Of Inflammation ◽

Increased Risk

Background and aim: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients. Materials and methods: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI (AIx@75), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure. Results: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher AIx@75 and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness. Conclusions: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD.

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