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Funding authority: Ministry of Research, Innovation and Digitization, Executive Agency for Higher Education, Research, Development and Innovation(UEFISCDI)

Project duration: 2021 - 2023

Director de proiect/Project director: Adrian Manea, Ph.D., Institute of Cellular Biology and Pathology "N. Simionescu", Bucharest, Romania (e-mail: adrian.manea@icbp.ro)

Rezumatul proiectului:

Ateroscleroza, cea mai frecventă boală cardiovasculară (BCV), reprezintă principala cauză de morbiditate și mortalitate la nivel mondial. Evenimentele asociate BCV pot fi prevenite la mai puțin de jumătate dintre pacienți prin implementarea strategiilor terapeutice convenționale. Dezvoltarea unor noi algoritmi terapeutici reprezintă o condiție esențială pentru reducerea impactului BCV. Epigenetica are un rol important in ateroscleroză. Metilarea histonelor reprezintă un marker epigenetic care poate fi transmisă prin mai multe cicluri celulare pentru a induce o memorie epigenetică toxică care ar putea explica eficiența slabă a terapiilor actuale la un număr mare de pacienți. Ipoteza noastră este că reprogramarea epigenetică prin țintirea farmacologică selectivă a enzimelor implicate în metilarea histonelor (KMT/KDM) ar putea reprezenta o strategie terapeutică importantă în ateroscleroză. Implicarea funcțională a KMT/KDM în ateroscleroză rămâne slab înțeleasă. În acest proiect ne propunem să descoperim rolul KMT/KDM și efectorilor lor moleculari cu scopul de a reduce progresia aterosclerozei mai eficient decât cu terapiile convenționale. Strategia integrează experimente pe probe biologice umane, modele in vitro și in vivo de ateroscleroză și tehnici avansate. Rezultate: 1) Panel validat al subtipurilor KMT și KDM ca biomarkeri și potențiale ținte terapeutice în ateroscleroză; 2) Strategie terapeutică validată preclinic bazată pe reprogramare epigenetică în ateroscleroză.

Project summary:

Atherosclerosis-related cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. The outcomes of CVD can be improved in less than a half of patients under conventional standards of care. The development of novel and comprehensive treatment algorithms is a prerequisite to limit the burden of CVD. Epigenetics has been mechanistically connected to atherosclerosis. Histone methylation marks can be transmitted through multiple cell cycles to induce the imprinting of a toxic epigenetic memory that could explain the poor effectiveness of the standard drugs in a large number of patients. We hypothesize that epigenetic reprogramming via pharmacological targeting of selective histone methylation enzymes (KMTs/KDMs) could represent an important therapeutic strategy in atherosclerosis. The functional implication of KMTs/KDMs in the pathoetiology of atherosclerosis remains elusive. In this project we aim to uncover the role of KMTs/KDMs and their down-stream molecular effectors in order to reduce atherosclerosis more effectively than conventional therapies. The proposed strategy entails experiments on human biological samples, in vitro and in vivo experimental models of atherosclerosis, and state-of-the-art techniques. Expected outcomes: 1) Validated panel of KMT and KDM subtypes as potential biomarkers and therapeutic targets in atherosclerosis; 2) Preclinical validated histone methylation reprogramming-based therapeutic strategy in atherosclerosis.

Publicatii/Publications

Peer-review ISI articles:

1. Lazar AG, Vlad ML, Manea A, Simionescu M, Manea SA. Activated histone acetyltransferase p300/CBP-related signalling pathways mediate up-regulation of NADPH oxidase, inflammation, and fibrosis in diabetic kidney. Antioxidants (Basel). 2021; 10(9):1356. doi: 10.3390/antiox10091356. Impact factor: 7.675.

2. Manea SA, Vlad ML, Lazar AG, Muresian H, Simionescu M, Manea A. Pharmacological inhibition of lysine-specific demethylase 1A reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice by a mechanism involving decreased oxidative stress and inflammation; potential implications in human atherosclerosis. Antioxidants (Basel), 2022; 11: 2382. https://doi.org/10.3390/antiox11122382.Impact factor:7.675.

Comunicari orale (Oral communications):

1. Manea A. Epigenetic mechanisms in cardiometabolic disorders: potential biomarkers and therapeutic targets. The 42nd Anniversary Symposium of the Institute of Cellular Biology and Pathology “Nicolae Simionescu” held jointly with 38^th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.

2. Manea A, Vlad ML, Lazar AG, Manea SA. Focused ultrasound-induced targeted delivery of miR-155-5p inhibitor employing biomimetic microbubbles reduces NADPH oxidase expression and inflammation in atherosclerotic ApoE-/- mice. Cardiovascular Research, 2022, Vol. 118, Supplement 1, pg. cvac066. 197.

3. Manea A, Vlad ML, Lazar AG, Manea SA. SET7 methyltransferase mediates the up-regulation of NADPH oxidase expression and oxidative stress in the atherosclerotic aorta of apolipoprotein E-deficient mice. Virchows Archiv (2022) 481 (Suppl 1):S157.

4. Manea A. Pathophysiological role and potential therapeutic implications of histone methylation-related epigenetic pathways in atherosclerosis. The 43nd Anniversary Symposium of the Institute of Cellular Biology and Pathology “Nicolae Simionescu”, 2022.

5. Lazar AG, Vlad ML, Manea A, Manea SA, Simionescu M. Ursolic acidreduces atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient mice by a mechanism involving decreased oxidative stress and inflammation. The 43nd Anniversary Symposium of the Institute of Cellular Biology and Pathology “Nicolae Simionescu”, 2022.

Postere prezentate la manifestări stiinţifice naţionale sau internaţionale (Posters presented at national and international meetings):

1. Manea A, Manea SA, Vlad LM, Lazar AG, Muresian H, Simionescu M. Identification of potential lysine-specific histone demethylase-dependent mechanisms underlying oxidative stress and inflammation in human and experimental atherosclerosis: a transcriptomics approach. The 45^th FEBS Congress 2021. FEBS OPEN BIO. 2021, 11, 142.

2. Lazar AG, Vlad LM, Manea A, Manea SA. Activation of histone acetyltransferase p300/CBP -dependent signaling pathways induces oxidative stress, inflammation, and fibrosis in the kidney of diabetic mice. The 38^th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.

3. Vlad LM, Lazar AG, Manea SA, Manea A. Histone demethylase KDM5B mediates the up-regulation of pro-oxidant and pro-inflammatory genes in M1-type macrophages. The 38^th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.

4. Manea SA, Lazar AG, Vlad ML, Manea A. Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice. Cardiovascular Research, 2022, Vol. 118, Supplement 1, pg. cvac066. 225.

5. Lazar AG, Vlad ML, Manea A, Olariu L, Manea SA. Ursolic acid reduces NADPH oxidase expression and ensuing oxidative stress in diabetic kidney. Atherosclerosis, 2022, Vol. 355, pg. 206.

6. Vlad ML, Mares RG, Lazar AG, Manea SA, Preda BM, Simionescu M, Schiopu A, Manea A. Monocyte-derived macrophages mediate S100a8/A9-induced oxidative stress and inflammation in the ischemic myocardium. Atherosclerosis, 2022, Vol 355, pg. 268.

7. Manea SA, Vlad ML, Lazar AG, Manea A. miR-210-3p mediates the up-regulation of NADPH oxidase expression in the atherosclerotic aorta of hypercholesterolemic apolipoprotein E-deficient mice; potential implications for human atherosclerosis. Atherosclerosis, 2022, Vol. 355, pg. 49-50.

8. Manea A, Manea SA, Vlad ML, Lazar AG, Muresian H, Simionescu M. Lysine-specific histone demethylase 1A mediates oxidative stress, inflammation, and atherogenesis in apolipoprotein E-deficient mice; prospective implications for human atherosclerosis. Atherosclerosis, 2022, Vol. 355, pg. 50.

9. Manea A, Vlad ML, Lazar AG, Manea SA. MicroRNA-210-3p contributes to inflammatory response in the atherosclerotic aorta of apolipoprotein E-deficient mice: potential role in human atherosclerosis. FEBS OPEN BIO, 2022, Vol. 12, pg. 152.

10. Manea SA, Lazar AG, Vlad ML, Manea A. Ursolic acid reduces NADPH oxidase expression and oxidative stress in the atherosclerotic aorta of apolipoprotein E-deficient mice by inhibiting NF-kB and STAT1/3 signaling. FEBS OPEN BIO, 2022, 12, pg. 151.

11. Manea SA, Lazar AG, Vlad ML, Manea A. Ursolic acid prevents the dysregulation in the expression of histone methylation-related epigenetic enzymes in diabetic kidney. Virchows Archiv (2022) 481 (Suppl 1): S86-S87.

12. Lazar AG, VladML, ManeaA, ManeaSA. Ursolic acid reduces inflammation and the development of atherosclerotic lesions in hypercholesterolemic apolipoprotein E-deficient mice. International Conference and XXXIX Scientific Session of the Romanian Society for Cell Biology, 2022.

13. Lazar AG, Vlad ML, Manea A, Olariu L, Manea SA. Ursolic acid reduces inflammation and oxidative stress in the kidney of diabetic mice. The 43nd Anniversary Symposium of the Institute of Cellular Biology and Pathology “Nicolae Simionescu”, 2022.

14. Vlad ML, Mares RG, Lazar AG, Manea SA, Preda BM, Simionescu M, Schiopu A, Manea A. Short-term pharmacological inhibition of alarmin S100A9 reduces oxidative stress and inflammation after myocardial infarction in mice. The 43nd Anniversary Symposium of the Institute of Cellular Biology and Pathology “Nicolae Simionescu”, 2022.