miR-24 and YKL-40 in Abdominal Aortic Aneurysm Lars Maegdefessel, MD - - PowerPoint PPT Presentation

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mir 24 and ykl 40 in abdominal aortic aneurysm
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miR-24 and YKL-40 in Abdominal Aortic Aneurysm Lars Maegdefessel, MD - - PowerPoint PPT Presentation

Oct 21, 2023 103 likes •252 views

miR-24 and YKL-40 in Abdominal Aortic Aneurysm Lars Maegdefessel, MD PhD, Uwe Raaz, MD PhD, Joshua M. Spin, MD PhD, Per Eriksson, PhD, Anders Hamsten, MD PhD, Philip S. Tsao, PhD Abdominal Aortic Aneurysm (AAA) Dilation of the infrarenal

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miR-24 and YKL-40 in Abdominal Aortic Aneurysm

Lars Maegdefessel, MD PhD, Uwe Raaz, MD PhD, Joshua M. Spin, MD PhD, Per Eriksson, PhD, Anders Hamsten, MD PhD, Philip S. Tsao, PhD

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Abdominal Aortic Aneurysm (AAA)

  • Dilation of the infrarenal aorta (> 3.0cm)
  • AAAs are common, lethal
  • 5-16% men; 1-2% women > 65y/o
  • Associated with atherosclerosis

– Family History – Age – Male Sex – Hypertension – History of Smoking – Diabetes (-)

  • No effective therapy for early disease
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Murine AAA Model: PPE Infusion

AAA Diameters Measured by US 0.60 0.80 1.00 1.20 1.40 1.60 1.80 Pre 3 14 Post-Operative Days Expansion in mm MALE 21 28 7 SALINE 10 FEMALE DIABETIC NICOTINE AGED

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Female Diabetes Nicotine Aged

87 93 97 97 65 42 72

microRNA Microarray - Mouse (Agilent™)

é é miR-21 ê ê miR-29b ê ê miR-23b-24-27b

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Gene Expression Microarray – Mouse (Agilent™)

Nicotine Aged Male Female Diabetes

éé éé 988 targets of the miR-23b-24-27b family

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miR-23b-24-27b and Targets in PPE-AAA

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Regulation of AAA by miR-24/YKL-40

miR-24 YKL-40 (phospho)-AKT Anti-apoptotic effects on macrophages, T-cells, eosinophils Cytokines Apoptotic

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Modulation of miR-24 in Mouse AAA

sham PPE + scr-miR PPE + anti-24 PPE + pre-24

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miR-24 Modulation in AngII-Induced AAA

1000 ng/min/kg of AngII for 28 days

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miR-24 Regulation in vitro

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miR and Gene Expression in Human AAA

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miR-24 and YKL-40 in Plasma

* * *

#

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Pathology of AAA - Therapeutic Opportunities

  • Transmural inflammation
  • SMC phenotypic changes and apoptosis
  • Impaired ECM remodeling
  • Loss of elastin layer integrity

à Progressive luminal expansion

miR-21 miR-29b miR-24

scr-miR pre-24

Sci Transl Med 2012 J Clin Invest 2012 unpublished

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Conclusions

  • microRNAs regulate gene expression in the aortic wall
  • miR-24 regulates inflammatory activity (and remodeling)

during AAA development via YKL-40

  • miR-24 and YKL-40 are differentially regulated in human

AAA tissue samples

  • YKL-40 is a novel biomarker of AAA disease severity
  • Modulating miR-24 represents a new therapeutic option to

control inflammatory processes during AAA development

  • Effect of systemic miR-24 modulation is yet unknown

à local delivery mechanisms desirable