B04-Extracellular vesicles as intercellular messengers in aortic valve calcification

Although aortic valve stenosis (AS) represents the most common type of valvular disease, its pathogenesis remains poorly understood. Recent evidence of the mechanisms of vascular disease and calcification-related processes indicates that extracellular vesicles (EVs) might play an important role in these processes. EVs are important mediators in intercellular communication and contain specific molecular cargoes, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that can modify specific cellular targets. Moreover, since vesicle composition and content reflect specific phenotypes/conditions of the releasing cells, EVs represent useful tools for diagnosing and monitoring cardiovascular as well as other diseases. However, the regulation of EV content and release and the mechanisms of interaction between EVs and the target cells involved in AS remain unclear. As there is accumulating evidence for the impact of EVs on endothelial cells and the vascular wall, EVs and their cargo might influence also the development of aortic aneurysms (AA).

Hypotheses

We hypothesize that EVs and EV-associated ncRNAs are actively involved in the regulation of aortic disease consisting of aortic valve stenosis and aortic aneurysms.

The initial goal of the proposed project is to explore the biological content and function of EVs under different conditions (calcifying vs. non-calcifying) and their contribution to valvular calcification processes. Both microvesicles and exosomes will be studied, with a focus on the miRNAs delivered by these EVs. In addition, also other noncoding (nc) RNA species will be analyzed. In Aim 1, we will analyze miRNA/lncRNA content in EVs isolated from AS patient samples. For this, we will collect blood and aortic valve tissue from diseased patients (Bonn Aortic Valve Tissue and Blood Bank). Hereby, we will profile EV-derived ncRNAs in these patients and find potential ncRNA candidates that will be analyzed in further detail for their pathophysiological function as well as their potential use as a biomarker for AS. In our preliminary experiments, we found that various miRNAs (miRNA-122, miRNA-92a) and lncRNAs (AGAP2-AS1, MALAT1) expressed in the aortic valve of diseased patients are differentially regulated compared to the control group. Aim 2 will focus on the contribution of EVs to valvular calcification in in vitro models. We will run target prediction analysis on EV-derived miRNAs and lncRNAs from Aim 1 and then test promising candidates in vitro to study their role and function during calcification. Aim 3 will focus on the role of pro-calcific vs. non-calcific EV-derived ncRNA in vivo. Specifically, we will test the development of AS following the gain- or loss-of-function of identified miRNA/lncRNA candidates in animal models. Additionally, we will investigate the contribution of EV-derived ncRNA on the development of AA within Aim 4 using a similar mechanistical approach as described for AS.

Our long-term objective is to elucidate ncRNA-controlled pathways during AS, which can be directly targeted using small molecules or RNA-based therapeutics. The detailed understanding of EV biology in AS and AA could also be used to directly deliver novel therapies to the location of disease, with the help of selectively loaded and specifically targeted EVs. Moreover, another long-term goal of this study is to implement valid ncRNA-based biomarkers for the occurrence and progression of aortic disease.

B04.png
© Sebastian Zimmer
CVD-EV-lncRNA
© Rabiul Hosen

Contacts

Avatar Jansen

PD Dr. Felix Jansen

Project leader B04

Heart Center, Building 26, room 152

Venusberg-Campus 2

53127 Bonn

Clinic for Internal Medicine II

+49 228 287-13619

Avatar Pfeifer

Prof. Dr. Alexander Pfeifer

Project leader B04

Biomedical Center I, Building 13, 2OG, room 14

Venusberg-Campus 1

53127 Bonn

Institute for Pharmacology and Toxicology

+49 228 287-51300

Avatar Goody

Dr. Philip Roger Goody

Postdoc

Biomedical Center I, Building 13, 1OG

Venusberg-Campus 1

53127 Bonn

Department of Molecular Cardiology and Institute for Pharmacology and Toxicology

+49 228 287-51481

Avatar Hosen

Dr.rer. nat. M. Rabiul Hosen

PhD

Independent Group Leader

Biomedical Center I, Building 13, 3OG

Venusberg-Campus 1

53127 Bonn

AG: Cardiovascular epigenetics, RNA Biology, and RNA-therapeutics

Molecular Cardiology, Heart Center Bonn

+49 228 287-51487

Avatar Zietzer

Dr. Andreas Zietzer

Postdoc

Biomedical Center I, Building 13, 3OG

Venusberg-Campus 1

53127 Bonn

Department of Molecular Cardiology

+49 228 287-51484

Avatar Nehl

Denise Nehl

PhD-Student

Biomedical Center I, Building 13, 3OG, room 14

Venusberg-Campus 1

53127 Bonn

Department of Molecular Cardiology

+49 228 287-51487

Avatar Mohammadi

Neda Mohammadi

PhD-Student

Biomedical Center I, Building 13, 1OG

Venusberg-Campus 1

53127 Bonn

Department of Pharmacology and Toxicology

+49 228 287-51256

Avatar Maus

Katharina Maus

PhD-Student

Biomedical Center I, Building 13, 3OG, room 14

Venusberg-Campus 1

53127 Bonn

Department of Molecular Cardiology

+49 228 287

BTA/MTA:
Ms. Anna Flender, BTA
Ms. Sarah Arahouan, BTA

MD Students:
Dr. med. Monika Baumschabl
Ms. Ling Zhou
Ms. Yujia Zhang
Ms. Zhexi Li
Mr. Yuan Zhou

Alumini:
Dr. med. Xu Xiang
Dr. med. Qian Li
Dr. med. Atur Illie
Dr. med. Yangyang Liu

Dr. Mona Malek Mohammadi, Dr. Sarah Rieck, Prof. Dr. Fleischmann (Institute for Physiology),
Dr. Staffan Hildebrand, Prof. Dr. Alexander Pfeifer (Institute for Pharmacology and Toxicology)
Prof. Dr. Farhad Baktiary (Department for Heart Surgery)
Prof. Dr. Bernardo Franklin, Prof. Dr. Eicke Latz (Institute for Innate Immunity)
Prof. Dr. Kerstin Welhelm-Jüngling (Endothelial Metabolism, Inst. Cardiovascular Science)
Prof. Dr. Kathrin Leppek (Clinical Chemistry and Clinical Pharmacology)
Dr. Marc Sylvester (Core Facility Mass Spectrometry, Medical Faculty)
Dr. Heimbach (Institute of Human Genetics, NGS core facility)
Prof. Dr. med. Sebastian Zimmer, PD. Dr. med. Felix Jansen, Dr. med. Philip Goody, Dr. med. Andreas Zietzer, Dr. med. Adem Aksoy, Dr. med. Baravan Al-Kassou (Heart Center Bonn)

Prof. Dr. Steven P. Jones (Diabetes and Obesity Center, University of Louisville, KY, USA)
Prof. Dr. Joseph B. Moore (Department of Medicine, The Christina Lee Brown Environment Institute, University of Louisville, KY, USA)
Prof. Dr. Shizuka Uchida (University of Aalborg, Copenhagen, Denmark)
Prof. Dr. Wenzel (System Biology, University of Bochum)
Dr. Ramesh Chennupati, Prof. Dr. Dr. med. Christian Jung (Cardiology, Pneumonology and Angiology, University Hospital Düsseldorf)
Dr. Giuseppe Militello (Yale University, CT, USA)
Dr. Tyler Weirick (RIKEN Institute, Japan)
Prof. Dr. Reinier Boon (Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands)
Prof. Dr. Stefanie Dimmeler (Institute for Cardiovascular Regeneration, University of Frankfurt)

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