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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: Acad. Maya Simionescu, Ph.D., Director, Institute of Cellular Biology and Pathology "N. Simionescu", Bucharest, Romania (e-mail: maya.simionescu@icbp.ro)

Research team:

Acad. Maya Simionescu, Ph.D.

Adrian Manea, Ph.D.

Simona-Adriana Manea, Ph.D.

Mihaela-Loredana Antonescu (Vlad), Ph.D. Student

Monica-Teodora Cosac (Master Student)

Summary of the project:

Despite the progresses in primary and secondary prevention, cardiovascular diseases (CVD) which entail the development of arterial atherosclerotic lesions remain the leading cause of morbidity and mortality worldwide. Thus, new approaches are essential to implement novel anti-atherosclerotic therapies. Recent data (including ours) demonstrated that monocyte-derived macrophages (Mac) actively orchestrate important inflammatory and oxidative reactions in atherosclerotic plaque formation. Two major Mac populations with distinct phenotypes have been described: the pro-inflammatory Mac (M1-Mac) and the anti-inflammatory Mac (M2-Mac). Consequently, the active induction of M2-Mac may be therapeutically relevant for the outcome of atherosclerosis. Emerging evidence indicates that epigenetic mechanisms, such as histone acetyltransferases (HAT) and histone deacetylases (HDAC)-regulated gene expression, play a role in the pathoetiology of CVD. The goal of this project is to find approaches to stimulate the generation of M2-Mac by modulating novel HAT and HDAC-dependent pathways. Subsequently, the specific HAT/HDAC isoforms could become novel pharmacological targets in atherosclerosis. The specific objectives are: (1) Analysis of HAT and HDAC-dependent epigenetic mechanisms implicated in Mac polarization – in vitro studies on mouse and human Mac. (2) Testing the selected HAT and HDAC isoforms implicated in M2-Mac polarization on ApoE-/- mice as potential therapeutic targets in atherosclerosis - preclinical in vivo studies. The expected outcomes are: (1) to provide novel and advanced knowledge on the mechanisms of Mac polarization within the atherosclerotic plaque; (2) to find the HAT/HDAC isoforms that promote the generation of M2-Mac in vitro and in vivo; and (3) an experimental platform for testing isoform-specific HAT/HDAC inhibitors to stimulate the induction of M2-Mac, with anti-atherosclerotic functions.

Specific objectives:

Objective 1. Analysis of HAT and HDAC-dependent epigenetic mechanisms implicated in Mac polarization – in vitro studies.

Objective 2. Testing the selected HAT and HDAC isoforms implicated in M2-Mac polarization on ApoE-/- mice as potential therapeutic targets in atherosclerosis- preclinical in vivo studies.

Expected results

Estimated results 2017:

- Functional model for in vitro investigation of epigenetic mechanisms of Mac polarization in atherosclerosis;

Estimated results 2018:

- Functional model for in vivo investigation of epigenetic mechanisms of Mac polarization in atherosclerosis;

- Novel HAT/HDAC isoforms that promote the generation of M2-Mac;

- 2 oral/poster communications at national/international meetings;

- 1 article submitted for publication in ISI journal;

- 1 article published in ISI journal;

Estimated results 2019:

- Experimental platform for development and testing of isoform-specific HAT/HDAC pharmacological inhibitors to induce alternatively activated M2-Mac with anti-atherosclerotic functions;

- 2 oral/poster communications at national/international meetings;

- 1 article submitted for publication in ISI journal;

- 1 article published in ISI journal.

Publications

Peer-review ISI articles:

1. Manea SA, Antonescu ML, Fenyo IM, Raicu M, Simionescu M, Manea A. Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes. Redox Biology 2018; 16:332-343. doi: 10.1016/j.redox.2018.03.011. Impact factor: 7.793.

2. 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: 4.868.

3. 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: 7.793.

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 12^th 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. Manea A. Epigenetic mechanisms in atherosclerosis: biomarkers and therapeutic targets. “ICBP Nicolae Simionescu - 40 years, Anniversary symposium”, Bucharest, 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 43^rd 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 43^rd 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 2018 – 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. 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.

17. 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.

18. 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.