Genetic Evidence for
            <i>PLASMINOGEN</i>
            as a Shared Genetic Risk Factor of Coronary Artery Disease and Periodontitis

Schäefer, Arne S.; Bochenek, Gregor; Jochens, Arne; Ellinghaus, David; Dommisch, Henrik; Güzeldemir-Akçakanat, Esra; Graetz, Christian; Harks, Inga; Jockel‐Schneider, Yvonne; Weinspach, Knut; Meyle, Joerg; Eickholz, Peter; Linden, Gerard J.; Çine, Naci; Nohutçu, Rahime M.; Weiss, Ervin I.; Houri‐Haddad, Yael; Iraqi, Fuad A.; Folwaczny, Mathias; Noack, Barbara; Strauch, Konstantin; Gieger, Christian; Waldenberger, Mélanie; Peters, Annette; Wijmenga, Cisca; Yılmaz, Engin; Lieb, Wolfgang; Rosenstiel, Philip; Doerfer, Christof; Bruckmann, Corinna; Erdmann, Jeanette; König, Inke R.; Jepsen, Søren; Loos, Bruno G.; Schreiber, Stefan

doi:10.1161/circgenetics.114.000554

Cited by 81 publications

(85 citation statements)

References 45 publications

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“…Mutation, abnormal expression, and mislocalization of vesicular transport proteins have been observed in various cardiovascular diseases, including atherosclerosis (22,23). However, there is only a limited understanding of the pathophysiology of vesiculartransport-associated cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm 2 ) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm 2 ), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm 2 ), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicleassociated membrane protein 3 (VAMP3) and synaptosomalassociated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern-specificity of SNARE activation and its contribution to the miRNA-mediated EC-SMC communication. T he interaction between hemodynamics and vascular endothelium is an important determinant of vascular homeostasis (1). In the straight part of the arteries, endothelial cells (ECs) are exposed to laminar blood flow with high shear stress that protects these parts of the vessels from atherogenesis, whereas in the branches and curvatures, the ECs experiencing disturbed flow with reciprocating and low shear stress stimulate the smooth muscle cells (SMCs) within the tunica media to become proliferative and migratory. The activated SMCs migrate into the intima, where they come into close contact with ECs and undergo phenotypic changes to lead to atherosclerosis (2). We recently demonstrated that vascular ECs repress expressions of forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 in the adjacent SMCs by producing microRNA-126-3p (miR-126-3p), and hence induce SMC turnover, and that the application of atheroprotective laminar shear (LS) at 12 dynes/cm 2 to ECs inhibits this paracrine effect (3). Although extracellular microRNAs (miRNAs) have been shown to convey messages from donor cells to recipient cells, how fluid shear stress regulates endothelial miRNA secretion remains to be elucidated.Emerging evidence has suggested that extracellular miRNAs can serve as not only pu...

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Section: Discussionmentioning

confidence: 99%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“… Shared genetic risk factors Obviously, there may be unknown shared risk factors of importance, including the genetic profile of patients with the two diseases. For example, a shared variant in the IL-1 gene complex could be part of the background for the simultaneous occurrence of both diseases, and recent studies have identified a number of other shared genetic risk factors [29,30]. However, these factors do not appear to explain the observed association fully.

PDIS, periodontitis; CVD, cardiovascular disease; AMI, acute myocardial infarction.

…”

Section: Explanatory Modelsmentioning

confidence: 99%

Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician

Holmstrup

Damgaard

Olsen

et al. 2017

Journal of Oral Microbiology

163

140

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Increasing evidence has suggested an independent association between periodontitis and a range of comorbidities, for example cardiovascular disease, type 2 diabetes, rheumatoid arthritis, osteoporosis, Parkinson’s disease, Alzheimer’s disease, psoriasis, and respiratory infections. Shared inflammatory pathways are likely to contribute to this association, but distinct causal mechanisms remain to be defined. Some of these comorbid conditions may improve by periodontal treatment, and a bidirectional relationship may exist, where, for example, treatment of diabetes can improve periodontal status. The present article presents an overview of the evidence linking periodontitis with selected systemic diseases and calls for increased cooperation between dentists and medical doctors to provide optimal screening, treatment, and prevention of both periodontitis and its comorbidities.

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“…In the latter study, variants within the IRF5 and PRDM1 genes were suggested to be associated with AgP, but not robustly validated; the proteins encoded by these genes play a role in interferon-beta signaling (76). In a similar fashion, recently new candidate genes for AgP were identified by exploring the well-established risk genes for coronary artery disease (CAD) (75). The CADassociated gene PLG (plasminogen), was significantly associated with AgP in both an explorative cohort and a validation cohort.…”

Section: Glt6d1 On Chromosomementioning

confidence: 99%

What is the Contribution of Genetics to Periodontal Risk?

Loos

Papantonopoulos

Jepsen

et al. 2015

Dental Clinics of North America

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This review addresses the multi-causal etiology of periodontitis, in which genetic factors play a role. The various proposed causes for periodontitis always play a role simultaneously, but the relative contribution of each of these, varies from case to case. In young individuals often with aggressive periodontitis (AgP) a stronger contribution from genetic factors is apparent, while in older individuals often with chronic periodontitis (CP), the relative contribution of the established subgingival biofilms (environmental factors) and life style factors (e.g. smoking, stress, diet), play a more dominant role in the phenotype of the disease.Nevertheless always some genetic susceptibility is present, for CP estimated at 25%.Periodontitis is therefore a complex disease, i.e. it behaves in a nonlinear fashion. Actually the disease progression rate fluctuates, where the disease sometimes moves into an aberrant state of host response and then swings back into a resolving state; in between, a settlement zone is present where essentially no differences are found for immunological parameters between cases with periodontitis and healthy controls. The genotype determines part of this fluctuation and the extent of it. The disease is polygenic, i.e. multiple genetic variants in multiple genes determine the phenotype, but there are individual and ethnic differences in the genes involved. We are still at the early stage to have identified the involved genes, in comparisons to other chronic diseases, we need to count on it that at least 100 causative genes across various global populations exist in AgP and CP. To date, the genetic variations firmly and repeatedly associated with periodontitis in some populations are found within the following genes: ANRIL, COX2, IL1, IL10, DEFB1, while many proposed periodontitis candidate genes have not been firmly proven or replicated. 3 KeypointsPeriodontitis is a multi-causal disease, with each of the causal factors playing a role but the relative contribution of these vary form case to case.The disease behaves in a nonlinear fashion, with periods of aberrant host response to periods within an active disease resolving state.To date only a few of the multitude of possible genetic factors for periodontitis are identified. Outline

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Genetic Evidence for PLASMINOGEN as a Shared Genetic Risk Factor of Coronary Artery Disease and Periodontitis

Cited by 81 publications

References 45 publications

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician

What is the Contribution of Genetics to Periodontal Risk?

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