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Project title:”Combined hormonal treatment-induced gene transactivation of anti-atherosclerotic proteins as an innovative therapeutic approach for atherosclerosis”.

Acronym: AterTE

Project team

Trusca Georgeta Violeta, Project Director

Gafencu Anca Violeta, Senior Researcher

Fenyo Ioana-Madalina, Postdoctoral Researcher

Dumitrescu Madalina, Postdoctoral Researcher

Tudorache Florina Irina, PhD student

Pruna Vasile, PhD

Project summary

Cardiovascular disease causes more that 55% of all deaths in Europe, hyperlipidaemia being a major contributor. The apolipoproteins have an important role in lipid metabolism.

The central hypothesis of this project claimed that thyroid and estrogen hormones agonists exert beneficial effects on the lipid metabolism and have anti-atherogenic properties at least through gene expression modulation of anti-atherosclerotic apolipoproteins. Thus, increasing the expression of apolipoproteins with therapeutic potential or inhibiting the activity of molecules that decrease the expression of these apolipoproteins will provide significant benefits in the fight against atherosclerosis.

The goal of this project was to determine the fine tuning of the apolipoprotein gene regulation by thyroid / glucocorticoid / estrogen hormones, in order to reduce the atherosclerotic process.

The main objectives of this project were the following:

1. To identify the molecular mechanisms involved in apolipoprotein gene regulation by estrogen / thyroid hormones. For this, we proposed the following activities:

i) identify the localization of the regulatory elements responsible for apolipoprotein gene modulation by thyroid / glucocorticoid / estrogen hormones,

ii) test the interaction of thyroid / glucocorticoid / estrogen hormone receptors with other factors and assess their role in apolipoprotein gene regulation,

iii) assess the effects of the endocrine disruptors on apolipoprotein expression by thyroid / estrogen hormones;

2. To determine the beneficial effects of combined hormonal treatments in experimental atherosclerosis, by:

i) assessment of the effects of combined hormonal treatments on lipid plasma levels in normal and atherogenic mice,

ii) evaluation of apolipoprotein gene modulation and investigation of atherosclerotic plaques development in mice receiving combined hormonal treatments.

The final results of this project identified the gene regulatory mechanisms of anti-atherosclerotic apolipoproteins by glucocorticoid / estrogen hormones.

Dissemination

Oral presentation at international scientific meetings:

- Transactivation of apolipoprotein E gene by thyroid hormones in macrophages, VG. Trusca, EV. Fuior, IF. Tudorache, C. Roman, D. Kardassis, AV. Gafencu, oral presentation at ”8^th National Congress with International Participation and 34^th Annual Scientific Session of the Romanian Society for Cell Biology”, 2016, Oradea

- ”Hormonal regulation of apolipoprotein E gene expression”, Violeta Georgeta Trusca, Elena Valeria Fuior, Ioana Mădălina Fenyo, Irina Florina Tudorache, Dimitris Kardassis, Maya Simionescu, Anca Violeta Gafencu, oral presentation at ”Al IX-lea Congres Național de Biologie Celulară și Moleculară cu participare internațională, a XXXV-a Sesiune Anuală a Societății Române de Biologie Celulară”, Iași, 2017.

-“The direct positive regulatory mechanism of glucocorticoids on apolipoprotein E expression in macrophages is obliterated in hepatocytes”, Violeta G. Trusca, Elena V. Fuior, Ioana M. Fenyo, Irina F. Tudorache, Dimitris Kardassis, Maya Simionescu, Anca V. Gafencu, oral presentation at „BIT’s 6^th World Congress of Endobolism 2017”, Czech Republic, Prague, July 12-14, 2017.

- “Transactivation of anti-atherosclerotic apolipoproteins as therapeutic approach for atherosclerosis”, Violeta Trusca, oral presentation at “EMBL: Analysis of Non-Coding RNAs: quaerite et invenietis”, Heidelberg, Germania, September 9-15, 2017.

Posters at national or international scientific meetings:

-”Apolipoprotein E upregulation by dexamethasone in macrophages”, VG. Trusca, EV. Fuior, IM. Fenyo, IF. Tudorache, D. Kardassis, M. Simionescu, AV. Gafencu–”2^nd Danube Conference on Epigenetics”, 2016, Budapest, Hungary

-”Cell-specific upregulation of apolipoprotein E gene expression in macrophages by glucocorticoids”, VG. Trusca, EV. Fuior, IM. Fenyo, IF. Tudorache, D. Kardassis, M. Simionescu, AV. Gafencu -”84th European Atherosclerosis Society Congress”, 2016, Innsbruck, Austria

-”Glucocorticoids upregulate apolipoprotein E gene expression in macrophages in a cell-specific manner”, V. Trusca, M. Fenyo, E. Fuior, I. Tudorache, D. Kardassis, M. Simionescu, A. Gafencu - Asociația Romana pentru Știința Animalelor de Laborator, 2016, Bucharest, Romania.

- “Regulation of apolipoproteins by ligand activated aryl hydrocarbon receptor“, autori Irina F. Tudorache, Violeta G. Trusca, Anca V. Gafencu - „BIT’s 6^thWorld Congress of Endobolism 2017”, Czech Republic, Prague, July 12-14 2017.

Papers:

- „Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes”, autori Roman C, Fuior EV, Trusca VG, Kardassis D, Simionescu M, Gafencu AV, Biochem Biophys Res Commun. 2015 Dec 4;468(1-2):190-5. doi: 10.1016/j.bbrc.2015.10.132. PubMed PMID: 26519880.

https://www.ncbi.nlm.nih.gov/pubmed/?term=26519880

- „Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes”, Trusca VG, Fuior EV, Fenyo IM, Kardassis D, Simionescu M, Gafencu AV., PLoS One. 2017 Mar 29;12(3):e0174078. doi:10.1371/journal.pone.0174078. eCollection 2017. PubMed PMID: 28355284; PubMed Central PMCID: PMC5371326.

https://www.ncbi.nlm.nih.gov/pubmed/?term=28355284

- „Apolipoprotein E - A Multifunctional Protein with Implications in Various Pathologies as a Result of Its Structural Features”, Tudorache IF, Trusca VG, Gafencu AV. Comput Struct Biotechnol J. 2017 Jun 6;15:359-365. doi:10.1016/j.csbj.2017.05.003. eCollection 2017.

https://www.ncbi.nlm.nih.gov/pubmed/?term=28660014