scholarly journals Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability

2021 ◽  
Author(s):  
Pavlos Tsantilas ◽  
Shen Lao ◽  
Zhiyuan Wu ◽  
Anne Eberhard ◽  
Greg Winski ◽  
...  
Keyword(s):  
At Risk ◽  
Smooth Muscle ◽  
Carotid Artery ◽  
Atherosclerotic Lesion ◽  
Adverse Outcomes ◽  
Plaque Burden ◽  
Cell Physiology ◽  
Mechanistic Studies ◽  
Plaque Vulnerability ◽  
Fibrous Cap

Abstract Aims  Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. Methods and results  Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. Conclusion  CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

scholarly journals Vascular smooth muscle cells in atherosclerosis: time for a re-assessment

2021 ◽  
Author(s):  
Mandy O J Grootaert ◽  
Martin R Bennett
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Atherosclerotic Lesion ◽  
Muscle Cells ◽  
Lineage Tracing ◽  
Phenotypic Switching ◽  
Fibrous Cap ◽  
The Media

Abstract Vascular smooth muscle cells (VSMCs) are key participants in both early and late-stage atherosclerosis. VSMCs invade the early atherosclerotic lesion from the media, expanding lesions, but also forming a protective fibrous cap rich in extracellular matrix to cover the ‘necrotic’ core. Hence, VSMCs have been viewed as plaque-stabilizing, and decreased VSMC plaque content—often measured by expression of contractile markers—associated with increased plaque vulnerability. However, the emergence of lineage-tracing and transcriptomic studies has demonstrated that VSMCs comprise a much larger proportion of atherosclerotic plaques than originally thought, demonstrate multiple different phenotypes in vivo, and have roles that might be detrimental. VSMCs down-regulate contractile markers during atherosclerosis whilst adopting alternative phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, myofibroblast-like, and mesenchymal stem cell-like. VSMC phenotypic switching can be studied in tissue culture, but also now in the media, fibrous cap and deep-core region, and markedly affects plaque formation and markers of stability. In this review, we describe the different VSMC plaque phenotypes and their presumed cellular and paracrine functions, the regulatory mechanisms that control VSMC plasticity, and their impact on atherogenesis and plaque stability.

3039Vulnerability of carotid atherosclerosis: relationship with plaque location, plaque eccentricity and vessel remodeling patterns. Insight from the the MAGNETIC observational study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O Catalano ◽  
C Cerabolini ◽  
E Eshja ◽  
G Bendotti ◽  
M De Salvo ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Wall Thickness ◽  
Carotid Atherosclerosis ◽  
Internal Carotid ◽  
Intraplaque Hemorrhage ◽  
Plaque Vulnerability ◽  
Cross Sectional ◽  
Fibrous Cap ◽  
Vessel Remodeling ◽  
Maximum Wall Thickness

Abstract Carotid atherosclerosis is a cause of brain ischemic events. Cardiovascular magnetic resonance (CMR) can assess plaque vulnerability. We investigated atherosclerosis vulnerability in relation to plaque location, eccentricity and vessel remodeling. Methods-Baseline CMR evaluations of the MAGNETIC observational study, were analyzed. We quantitated with MRI-Plaque View™, vessel lumen/wall and vulnerable plaque components of a 32-mm segment of common carotid artery (12 mm), bulb (8 mm) and internal carotid artery (12 mm). Lipid-rich necrotic core [LRNC], fibrous cap [CAP] and intraplaque hemorrhage [IPH] were expressed as percent of wall area. Results-A data-set of 8080 sections of adequate quality in 260 patients (198 male [76%], median age 71 years [65–76]), were analyzed. Patients were on therapy with antiplatelet, ACE-inhibitors/ARB and statins (196–229 out of 260 [75–88%]). We found significant differences in plaque composition according to longitudinal and circumferential location, eccentricity and vessel remodeling (table). At multivariate regression analysis, including classical RF and atherosclerotic burden, we found an independent association of: LRNC and IPH with longitudinal location, eccentricity and positive remodeling, and of CAP with eccentricity (p<0.001 for all). Lipid-rich necrotic core Fibrous cap Intraplaque hemorrhage Longitudinal distribution Common carotid artery 4% [1–10] p<0.001 6% [4–11] p<0.001 0% [0–3] p<0.001 Carotid bulb 7% [3–13] 9% [5–13] 1% [0–4] Internal carotid artery 3% [0–10] 7% [4–11] 0% [0–1] Circunferenzial location Antero-medial 4% [0–11] p<0.001 7% [4–12] p=0.07 0% [0–2] p<0.001 Antero-lateral 6% [1–12] 8% [5–12] 1% [0–4] Postero-lateral 5% [0–11] 7% [4–12] 0% [0–3] Postero-medial 5% [0–11] 7% [4–12] 0% [0–1] Plaque eccentricity Concentric 3% [0–9] p<0.001 7% [4–11] p<0.001 0% [0–2] p<0.001 Eccentric 9% [4–15] 9% [5–13] 1% [0–4] Remodelling pattern Negative 4% [0–10] p<0.001 7% [4–11] p<0.001 0% [0–2] p<0.001 Positive 7% [3–13] 8% [5–13] 1% [0–4] Plaque eccentricity was defined as eccentricity index (EI = [maximum wall thickness − minimum wall thickness]/maximum wall thickness) in the highest quartile. Positive remodeling was defined as remodeling index (= [vessel cross-sectional area − reference area]/cross-sectional area) in the highest quartile. Conclusions Carotid atherosclerotic plaque vulnerability seems to be independently associated with longitudinal location, plaque eccentricity and vessel positive remodeling. Acknowledgement/Funding Bayer AG, Leverkusen, Germany

Abstract 95: MiRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Suzanne M Eken ◽  
Hong Jin ◽  
Ekaterina Chernogubova ◽  
Yuhuang Li ◽  
Nancy Simon ◽  
...  
Keyword(s):  
At Risk ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Cell Survival ◽  
Vascular Disease ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions

In the search for markers and modulators of vascular disease, miRNAs have emerged as potent therapeutic targets. We investigated miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. Utilizing patient material from the Biobank of Karolinska Endarterectomies (BiKE), we profiled miRNA expression in symptomatic versus asymptomatic patients with high-grade carotid artery stenosis. A PCR-based miRNA of plasma, sampled at the carotid lesion site, identified eight deregulated miRNAs (miR-15b, -29c, -30c/d, -150, -191, -210 and -500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser-capture microdissection as well as in situ hybridization revealed a distinct localization of miR-210 in the fibrous caps of atherosclerotic lesions and showed reduced miR-210 expression in the unstable fibrous cap. We confirmed that miR-210 directly targets the tumor suppressor gene adenomatous polyposis coli (APC), thereby affecting Wnt signaling and regulating vascular smooth muscle cell survival, as well as differentiation, in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in two rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. We discovered that an unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring vascular smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic disease.

scholarly journals Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms

2021 ◽  
Vol 3 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Alexandra A. C. Newman ◽  
Vlad Serbulea ◽  
Richard A. Baylis ◽  
Laura S. Shankman ◽  
Xenia Bradley ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cell Types ◽  
Fibrous Cap ◽  
Multiple Cell

scholarly journals Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Shanshan Liu ◽  
Xiuxin Jiang ◽  
Xiuru Cui ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiovascular Events ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Plaque Burden ◽  
Atherosclerotic Plaques ◽  
Ampk Activation ◽  
Homeostatic Regulation ◽  
Human Antigen R

AbstractHuman antigen R (HuR) is a widespread RNA-binding protein involved in homeostatic regulation and pathological processes in many diseases. Atherosclerosis is the leading cause of cardiovascular disease and acute cardiovascular events. However, the role of HuR in atherosclerosis remains unknown. In this study, mice with smooth muscle-specific HuR knockout (HuRSMKO) were generated to investigate the role of HuR in atherosclerosis. HuR expression was reduced in atherosclerotic plaques. As compared with controls, HuRSMKO mice showed increased plaque burden in the atherosclerotic model. Mechanically, HuR could bind to the mRNAs of adenosine 5′-monophosphate-activated protein kinase (AMPK) α1 and AMPKα2, thus increasing their stability and translation. HuR deficiency reduced p-AMPK and LC3II levels and increased p62 level, thereby resulting in defective autophagy. Finally, pharmacological AMPK activation induced autophagy and suppressed atherosclerosis in HuRSMKO mice. Our findings suggest that smooth muscle HuR has a protective effect against atherosclerosis by increasing AMPK-mediated autophagy.

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