National Grants
PN-III-P1-1.1-TE-2016-0851
Project title:Preclinical strategy to reduce vascular inflammation and oxidative stress by targeting novel non-coding RNA pathways in atherosclerosis
Acronym: RNATHER
Project code: PN-III-P1-1.1-TE-2016-0851; Contract number: 51/2018
Contracting authority: Ministry of Research and Innovation - Executive Agency for Higher Education, Research, Development and Innovation (MCI-UEFISCDI)
Contractor: Institute of Cellular Biology and Pathology “Nicolae Simionescu”
Project director: Adrian Manea, Ph.D., Head of Molecular and Cellular Pharmacology - Functional Genomics Laboratory, Institute of Cellular Biology and Pathology "N. Simionescu", Bucharest, Romania (e-mail: adrian.manea@icbp.ro)
Research team:
Adrian Manea, Ph.D.
Ioana Madalina Fenyo, PhD.
Simona-Adriana Manea, Ph.D.
Mihaela-Loredana Antonescu (Vlad), Ph.D. Student
Alexandra-Gela Lazar, Ph.D. Student
Summary of the project:
Cardiovascular diseases are the leading cause of morbidity and mortality in the world and have a profound social and economical impact regardless of the achievements in the primary and secondary prevention strategies. Atherosclerosis, the most common chronic vascular disorder, affects the structure and function of the arterial walls. Recent data (including ours) demonstrated that inflammation and oxidative stress are critically involved in the atheroma formation and destabilization of vulnerable plaque. Left untreated, atherosclerosis predispose to major cardiovascular events such as stroke, myocardial infarction, heart failure, and sudden death. Thus, there is a stringent need for the development of specific atherosclerotic plaque-oriented therapies to significantly reduce the incidence of major cardiovascular events. Evidence exists that microRNAs may be effective therapeutic targets in atherosclerosis. Yet, the role of miRNAs in vascular pathobiology represents an open issue. Mimicking of anti-atherogenic miRNAs and/or blocking the pro-atherogenic miRNAs could become a reliable intervention in cardiovascular clinical practice. The goal of this project is to identify and functionally characterize miRNAs underlying vascular inflammation and oxidative stress in order to develop novel nanotechnology-based miRNA therapeutics in atherosclerosis. The specific objectives: (1) Identification of miRNAs underlying vascular inflammation and oxidative stress in atherosclerosis - in vitro and in vivo studies. (2) Molecular targeting of selected inflammation and oxidative stress-related miRNAs to reduce atherosclerotic plaque development - preclinical in vitro and in vivo studies. The expected outcomes: (1) A new panel of in vivo validated miRNAs that may serve as biomarkers, therapeutic targets and/or therapeutic agents in atherosclerosis; (2) A novel preclinical nanotechnology-based strategy to reduce the development of atheroma by modulating key miRNA-related pathways.
Specific objectives:
Objective 1. Identification of miRNAs underlying vascular inflammation and oxidative stress in atherosclerosis - in vitro and in vivo studies.
Objective 2. Molecular targeting of selected inflammation and oxidative stress-related miRNAs to reduce atherosclerotic plaque development – preclinical in vitro and in vivo studies.
Expected results
Estimated results 2018:
- In vitro model for investigation of miRNA-based pathways in atherosclerosis. Validated miRNA panel expressed by vascular cells or immune cells (monocytes/macrophages) in response to pro-atherogenic conditions in vitro;
- Scientific report;
- WEB page.
Estimated results 2019:
- 1 oral/poster communication at a national/international meeting;
- 1 article submitted for publication in ISI journal;
- In vivo model for investigation of miRNA-based pathways in experimental atherosclerosis. In vivo validated miRNA expression panel in experimental and human atherosclerosis;
- Scientific report;
- WEB page.
Estimated results 2020:
- 1 oral/poster communication at a national/international meeting;
- 1 article published in ISI journal;
- Preclinical miRNA-based therapeutic strategy to reduce atheroma formation;
- Scientific report;
- WEB page.
Publications
Peer-review ISI articles:
1. Vlad ML,Manea SA,Lazar AG,Raicu M, Muresian H,Simionescu M,Manea A. Histone acetyltransferase-dependent pathways mediate upregulation of NADPH oxidase 5 in human macrophages under inflammatory conditions: a potential mechanism of reactive oxygen species overproduction in atherosclerosis. Oxidative Medicine and Cellular Longevity 2019; Volume 2019, Article ID 3201062, 17 pages. doi.org/10.1155/2019/3201062. Impact Factor: 5.076.
2. Manea SA, Vlad ML, Fenyo IM, Lazar AG, Raicu M, Muresian H, Simionescu M, Manea A. Pharmacological inhibition of histone deacetylase reduces NADPH oxidase expression, oxidative stress and the progression of atherosclerotic lesions in hypercholesterolemic apolipoprotein E-deficient mice; potential implications for human atherosclerosis. Redox Biology, 28:101338, 1-13, 2019. Impact Factor: 9.986.
Manuscripts in preparation:
1. Manea SA, Vlad ML, Lazar AG, Muresian H, Simionescu M, Manea A. Identification and functional annotation of novel microRNAs in human atherosclerosis; unveiling potential mechanisms underlying viral infection of the vascular cells.
Oral communications:
1. Manea A. Pharmacological inhibition of histone deacetylase mitigates markers of oxidative stress and inflammation in hypercholesterolemic apolipoprotein E deficient mice. “European Atherosclerosis Society Congress 2018 – 86th EAS Congress”. Science at a Glance Section, Portugal, 2018.
2. Manea SA. Ex vivo detection of vascular reactive oxygen species formation in atherosclerotic ApoE-/- mice by high resolution near-infrared fluorescence imaging. “European Atherosclerosis Society Congress 2018 – 86th EAS Congress”. Science at a Glance Section, Portugal, 2018.
3. Manea A. Histone deacetylases as potential therapeutic targets in atherosclerosis. “The 12th Central and Eastern European Proteomic Conference”, Bucharest, 2018.
4. Manea A. Simionescu M. Histone deacetylases, potential therapeutic targets in diabetes-associated vascular disorders - preclinical predictions. “International Conference on Interdisciplinary Management of Diabetes Mellitus and its Complications – INTERDIAB”, Bucharest, 2019.
5. Lazar A., CosacMT., VladML., ManeaA., ManeaSA. Cross-communication between histone acetyltransferase and histone deacetylase epigenetic enzymes augments oxidative stress and fibrosis in the kidney of diabetic mice. “European Atherosclerosis Society Congress 2019 – 87th EAS Congress”. Science at a Glance Section, Netherlands, 2019.
6. Manea A. Epigenetic mechanisms in atherosclerosis: biomarkers and therapeutic targets. “ICBP Nicolae Simionescu - 40 years, Anniversary symposium”, Bucharest, 2019.
7. Manea A., Simionescu M. Mecanisme epigenetice in ateroscleroza: biomarkeri si potentiale tinte terapeutice. “A 3-a Sesiune Stiintifica Anuala a Academiei de Stiinte Medicale - De la medicina moleculara la medicina clinica”,Bucuresti, 2019.
Posters:
1. Antonescu ML, Manea SA, Muresian H, Manea A, Simionescu M. Up-regulation of macrophage NADPH oxidase 5 expression and reactive oxygen species production by histone acetyltransferase-dependent mechanisms in atherosclerosis. “Protecting the Code: Epigenetic Impacts on Genome Stability”, 2017.
2. Manea SA, Antonescu ML, Lazar A, Fenyo IM, Manea A. Pharmacological inhibition of histone acetyltransferase reduces endothelin-1 expression and mitigates markers of vascular dysfunction in diabetes. “European Society for Pharmacogenomics and Personalized Therapy, 4th Conference”, 2017.
3. Antonescu ML, Lazar AG, Manea SA, Raicu M, Muresian H, Simionescu M, Manea M. Pharmacological inhibition of NADPH oxidase down-regulates the expression of pro-inflammatory markers in classically-activated macrophages in vitro: potential implication in human atherosclerosis. “1st Olympiad in Cardiovascular Medicine - International Symposium on Experimental & Clinical Cardiovascular Medicine”, 2018.
4. Lazar AG, Antonescu ML, Fenyo IM, Manea A, Manea SA. Histone acetyltransferase-dependent signaling pathways mediate the up-regulation of endothelin-1 and markers of vascular dysfunction in experimental diabetes. “1st Olympiad in Cardiovascular Medicine - International Symposium on Experimental & Clinical Cardiovascular Medicine”, 2018.
5. Manea SA, Antonescu ML, Stan D, Lazar AG, Raicu M, Calin M, Manea A. High resolution near-infrared fluorescence imaging of reactive oxygen species overproduction associated with atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice. “The 36th Annual Scientific Session of the Romanian Society for Cell Biology and the 10th National Congress with International participation”, 2018.
6. Antonescu ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M. Epigenetic control of macrophage polarization by histone acetylation/deacetylation enzymes in experimental atherosclerosis. “The 36th Annual Scientific Session of the Romanian Society for Cell Biology and the 10th National Congress with International participation”, 2018.
7. Manea SA, Antonescu ML, Stan D, Lazar AG, Calin M, Manea A. Ultrasound-based imaging of reactive oxygen species overproduction associated with atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice. “The 43rd FEBS Congress”, 2018.
8. Manea A, Manea SA, Antonescu ML, Lazar AG, Muresian H, Maya Simionescu. Epigenetic regulation of inflammatory macrophage polarization by histone deacetylase-dependent mechanisms in experimental atherosclerosis. “The 43rd FEBS Congress”, 2018.
9. Antonescu (Vlad) ML, Lazar AG, Manea SA, Raicu M, Muresian H, Simionescu M, Manea A. Up-regulated NADPH oxidase-derived reactive oxygen species induce macrophage polarization towards M1 phenotype in vitro; potential implication in human atherosclerosis. „The 12th Central and Eastern European Proteomic Conference”, 2018.
10. Manea A, Manea SA, Vlad ML, Lazar AG, Cosac MT, Simionescu M. P300/CBP-histone acetyltransferase mediates the up-regulation of NADPH oxidase expression and oxidative stress in the aorta of diabetic mice.“7th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension”,2019.
11. ManeaSA, LazarAG, VladML, CosacMT, Manea A.Induction of histone deacetylase signaling pathways augments vascular inflammation and remodeling in diabetic mice. “7th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension”,2019.
12. Vlad ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M, Manea A. NADPH oxidase – derived reactive oxygen species augment inflammatory macrophage responses via redox-sensitive histone deacetylase-dependent epigenetic mechanisms in experimental atherosclerosis. “European Atherosclerosis Society Congress 2019 – 87th EAS Congress”. 2019.
13. Manea A, Manea SA, Vlad ML, Lazar AG, Cosac MT, Simionescu M. Histone deacetylase subtypes are part of positive feedback mechanisms controlling their own expression in the atherosclerotic aorta of hypercholesterolemic ApoE-/- mice. “29th European Meeting on Hypertension and Cardiovascular Protection”, 2019.
14. ManeaSA, Vlad ML, Lazar AG, Fenyo IM, Cosac MT, Manea A. Identification of novel microRNAs associated with atherosclerotic lesion formation in the aorta of hypercholesterolemic ApoE-/- mice; potential implications for human atherosclerosis.“29th European Meeting on Hypertension and Cardiovascular Protection”, 2019.
15. Vlad ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M, Manea A. Activation of histone acetyltransferase-dependent signaling pathways induces macrophage polarization towards a pro-inflammatory M1-like phenotype in vitro; potential implication in human atherosclerosis. “The 11th National Congress with International Participation and the 37th Annual Scientific Session of the Romanian Society of Cell Biology”, 2019.
16. Lazar AG, Cosac MT, Vlad ML, Raicu M, Manea A, Manea SA. Activation of p300 histone acetyltransferase-dependent signaling pathways induces NADPH oxidase expression and oxidative stress in the kidney of diabetic mice. “The 11th National Congress with International Participation and the 37th Annual Scientific Session of the Romanian Society of Cell Biology”, 2019.
17. Cosac MT, Vlad ML, Manea SA, Lazar AG, Raicu M, Simionescu M, Manea A. Pharmacological inhibition of histone lysine demethylase JARID1b down-regulates the expression of pro-inflammatory molecules in cultured M1-polarized human macrophages. “The 11th National Congress with International Participation and the 37th Annual Scientific Session of the Romanian Society of Cell Biology”, 2019.
18. Vlad ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M, Manea A. Epigenetic regulation of NADPH oxidase 5 expression by histone acetyltransferase-activated mechanisms in human macrophages exposed to inflammatory conditions; potential role in atherosclerosis. “ICBP Nicolae Simionescu - 40 years, Anniversary symposium”, 2019.
19. Lazar AG, Cosac MT, Vlad ML, Raicu M, Manea A, Manea SA. Activation of p300 histone acetyltransferase-dependent signaling pathways induces NADPH oxidase expression and oxidative stress in the kidney of diabetic mice. “ICBP Nicolae Simionescu - 40 years, Anniversary symposium”, 2019.
20. Manea SA, Vlad ML, Lazar AG, Cosac MT, Muresian H, Simionescu M, Manea A. Novel microRNAs associated with advanced human atherosclerotic lesions - potential biomarkers and therapeutic targets. “5th ESPTCongress - Precision Medicine and Personalised Health”, 2019.
Awards
2019 - First prize for poster presentation: “Activation of p300 histone acetyltransferase-dependent signaling pathways induces NADPH oxidase expression and oxidative stress in the kidney of diabetic mice”. Autori: Alexandra-Gela Lazar, Monica-Theodora Cosac, Mihaela-Loredana Vlad, Monica Raicu, Adrian Manea, Simona-Adriana Manea. The 11th National Congress with International Participation and the 37th Annual Scientific Session of the Romanian Society of Cell Biology, 2019, Constanta.
