A Redox-Responsive Self-Assembled Nanoprobe for Photoacoustic Inflammation Imaging to Assess Atherosclerotic Plaque Vulnerability

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.

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The impact of Mediterranean diet on coronary plaque vulnerability, microvascular function, inflammation, and microbiome after an acute coronary syndrome: study protocol for the MEDIMACS randomized, controlled, mechanistic clinical trial.

10.21203/rs.3.rs-317853/v1 ◽

2021 ◽

Author(s):

Ana I Fernandez ◽

Javier Bermejo ◽

Raquel Yotti ◽

Miguel Ángel Martínez-Gonzalez ◽

Alex Mira ◽

...

Keyword(s):

Clinical Trial ◽

Acute Coronary Syndrome ◽

Mediterranean Diet ◽

Atherosclerotic Plaque ◽

High Intensity ◽

Plaque Vulnerability ◽

Diet Intervention ◽

Coronary Syndrome ◽

Randomized Controlled ◽

The Impact

Abstract Background: Primary prevention trials have demonstrated that the traditional Mediterranean diet is associated with a reduction in cardiovascular mortality and morbidity. However, this benefit has not been proven for secondary prevention after an acute coronary syndrome (ACS). We hypothesized that a high-intensity Mediterranean diet intervention after an ACS decreases the vulnerability of atherosclerotic plaques by complex interactions between anti-inflammatory effects, microbiota changes and modulation of gene expression. Methods: The MEDIMACS project is an academically funded, prospective, randomized, controlled and mechanistic clinical trial designed to address the effects of an active randomized intervention with the Mediterranean diet on atherosclerotic plaque vulnerability, coronary endothelial dysfunction, and other mechanistic endpoints. One hundred patients with ACS are randomized 1:1 to a monitored high-intensity Mediterranean diet intervention or to standard-of-care arm. Adherence to diet is assessed in both arms using food frequency questionnaires and biomarkers of compliance. The primary endpoint is the change (from baseline to 12 months) in the thickness of the fibrous cap of a non-significant atherosclerotic plaque in a non-culprit vessel, as assessed by repeated optical-coherence-tomography intracoronary imaging. Indices of coronary vascular physiology and changes in gastrointestinal microbiota, immunological status, and protein and metabolite profiles will be evaluated as secondary endpoints. Discussion: The results of this trial will address the key effects of dietary habits on atherosclerotic risk and will provide initial data on the complex interplay of immunological, microbiome-, proteome- and metabolome-related mechanisms by which non-pharmacological factors may impact the progression of coronary atherosclerosis after an ACS.Trial registration: ClinicalTrials.gov, NCT03842319. Registered on 13 May 2019. https://clinicaltrials.gov/ct2/show/NCT03842319

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Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability

International Journal of Molecular Sciences ◽

10.3390/ijms19092621 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2621

Author(s):

Maxime Pellegrin ◽

Karima Bouzourène ◽

Jean-François Aubert ◽

Aimable Nahimana ◽

Michel Duchosal ◽

...

Keyword(s):

Bone Marrow ◽

Mrna Expression ◽

Atherosclerotic Plaque ◽

Cholesterol Metabolism ◽

Mrna Levels ◽

Ang Ii ◽

Plaque Vulnerability ◽

Plaque Development ◽

Pro Inflammatory Cytokines

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE−/− mice transplanted with AT1aR−/− or AT1aR+/+ BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR−/− BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR−/− BM 2K1C mice (−79% in the aortic sinus and −71% in whole aorta compared to controls). Plaques from AT1aR−/− BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (−82% and −88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR−/− BM 2K1C mice. No significant differences in either the number of circulating Ly6Chigh inflammatory monocytes and Ly6Clow resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability.

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Abstract 16121: Recombinant Human Placental Growth Factor 2 is a Safe and Effective Therapy for Ischemic Cardiomyopathy in Atherosclerotic Mice

Circulation ◽

10.1161/circ.130.suppl_2.16121 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ming Wu ◽

Melissa Swinnen ◽

Ellen Caluwe ◽

Hilde Gillijns ◽

Nina Vanden Driessche ◽

...

Keyword(s):

Growth Factor ◽

Atherosclerotic Plaque ◽

Ischemic Cardiomyopathy ◽

Contractile Function ◽

Left Ventricular ◽

Placental Growth Factor ◽

Plaque Burden ◽

Lv Function ◽

Plaque Vulnerability ◽

Adverse Remodeling

Aim: Angiogenic growth factor therapy carries a risk of stimulating atherosclerotic plaque growth. We evaluated whether systemic infusion of recombinant human placental growth factor (rhPlGF) 2 improves myocardial neovascularization, left ventricular (LV) function and adverse remodeling in a murine model of advanced atherosclerosis and chronic myocardial infarction (MI) without increasing atherosclerotic plaque size and plaque vulnerability. Methods: ApoE -/- mice were fed a high cholesterol diet and MI was induced 4 weeks (w) later using 60 min LAD occlusion followed by reperfusion. After 8 w, we assessed LV function using echocardiography and randomized mice to receive rhPlGF2 (450μg/kg/day, n=20) or PBS (n=20) via osmotic minipumps for 28 days. Echocardiography and histological analyses were performed at 12 and 20 w. Results: Infusion of rhPlGF2 increased PlGF plasma levels for 3 w up to ~1600-fold without adverse side effects, or changes in total cholesterol and high sensitive CRP levels. In rhPlGF2-treated mice, capillary and arteriolar density was significantly higher in ischemic myocardium (2813±212 capillaries/mm 2 at 12 w vs 2144±478 in PBS, P <0.05; 125±18 arterioles/mm 2 at 20 w vs 77±13 in PBS, P =0.001). RhPlGF2 significantly improved ejection fraction (EF), reduced LV end-systolic and end-diastolic volume indices at 12 w and prevented further LV dilation and EF deterioration at 20 w (Figure). RhPlGF2 did not increase plaque area in the aortic arch, or the degree of fibrosis, calcification, capillary or arteriolar density and MAC3-positive cell areas in plaques at 12 and 20 w. Conclusion: Systemic rhPlGF2 infusion significantly improves neovascularization and contractile function, and prevents LV adverse remodeling in chronic ischemic cardiomyopathy without increasing atherosclerotic plaque burden or plaque vulnerability. RhPlGF2 may represent a promising and safe therapeutic strategy in chronic ischemic cardiomyopathy.

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P6473Impact of myocardial bridging on atherosclerotic plaque vulnerability assessed by OCT

European Heart Journal ◽

10.1093/eurheartj/ehx493.p6473 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

R. Yamada ◽

T. Kume ◽

T. Koyama ◽

K. Imai ◽

T. Tamada ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Plaque Vulnerability ◽

Myocardial Bridging

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4. Redox-Responsive Self-Assembled Amphiphilic Materials: Review and Application to Biological Systems

Advanced Materials ◽

10.1515/9783110537734-004 ◽

2019 ◽

pp. 113-142

Keyword(s):

Biological Systems ◽

Redox Responsive ◽

Self Assembled

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Macrophage polarisation in shear stress modulated atherosclerotic plaque vulnerability

Atherosclerosis ◽

10.1016/j.atherosclerosis.2012.10.005 ◽

2012 ◽

Vol 225 (2) ◽

pp. e2 ◽

Cited By ~ 1

Author(s):

Anusha N. Seneviratne ◽

Jennifer E. Cole ◽

Michael E. Goddard ◽

Zahra Mohri ◽

Rob Krams ◽

...

Keyword(s):

Shear Stress ◽

Atherosclerotic Plaque ◽

Plaque Vulnerability ◽

Macrophage Polarisation

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A star-shaped amphiphilic block copolymer with dual responses: synthesis, crystallization, self-assembly, redox and LCST–UCST thermoresponsive transition

Polymer Chemistry ◽

10.1039/c6py00702c ◽

2016 ◽

Vol 7 (30) ◽

pp. 4901-4911 ◽

Cited By ~ 8

Author(s):

Hua Yuan ◽

Hai Chi ◽

Weizhong Yuan

Keyword(s):

Block Copolymer ◽

Self Assembly ◽

Amphiphilic Block Copolymer ◽

Redox Responsive ◽

Self Assembled

The micelles/aggregates that were self-assembled from a star-shaped copolymer presented redox-responsive behaviour and LCST–UCST thermoresponsive transition.

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