National Grants
Project code: PN-III-P2-2.1-PED-2019-2497
Contract number: 342PED/2020
Project title: Advanced theranostic strategy in atherosclerosis integrating pharmaco-epigenomic interventions and biomimetic microbubbles as ultrasound-mediated targeted drug delivery systems
Acronym: ECHOTHERA
Project duration: 03/08/2020 - 28/10/2022
Project director: Dr. Adrian Manea
Abstract
Atherosclerosis-related cardiovascular diseases (CVD) are the main cause of morbidity and mortality worldwide. According to the most recent statistics, the outcomes of CVD can be improved in less than a half of patients under conventional standards of care. Thus, the development of alternative, advanced, specific, straightforward, and cost-efficient therapeutic interventions is a prerequisite to limit and burden of CVD at economic and societal level. Emerging clinical and experimental evidence (including ours) indicates that the dysregulation of specific epigenetic systems is mechanistically connected to atherosclerotic plaque formation and destabilization. Our hypothesis is that targeted and personalized treatment of atherosclerosis function of the patient epigenetic profile could be more effective than the currently employed conventional therapeutic interventions. The scope of the project is to develop and validate under laboratory conditions an innovative theranostic strategy integrating pharmaco-epigenomic interventions and sterically stabilized biomimetic microbubbles as focused ultrasound-responsive targeted drug delivery systems in an attempt to specifically concentrate the pharmacological active compounds at the sites of atherosclerotic lesions with minimal off-target and side effects. The proposed strategy entails a systematic set of experiments employing state-of-the-art and highly synergistic methodology and in vitro and in vivo experimental models of atherosclerosis. Expected outcomes: (1) Optimized protocol to obtain biomimetic microbubbles encapsulating epigenetic-oriented drugs in a highly purified and standardized state required for pharmaceutical applications; (2) Laboratory validated theranostic strategy in atherosclerosis integrating pharmaco-epigenomic interventions and sterically stabilized biomimetic microbubbles as focused ultrasound-responsive targeted drug delivery systems.
Objectives:
Objective 1: Development of an innovative epigenetic-oriented drug delivery system employing ultrasound-sensitive sterically stabilized biomimetic microbubbles.
Objective 2: Preclinical validation of the epigenetic-oriented, ultrasound-based theranostic strategy to reduce the severity of atherosclerotic lesions.
Dissemination:
Articles
1. Manea SA, Vlad ML, Rebleanu D, Lazar AG, Fenyo IM, Calin M, Simionescu M, Manea A. Detection of vascular reactive oxygen species in experimental atherosclerosis by high-resolution near-infrared fluorescence imaging using VCAM-1-targeted liposomes entrapping a fluorogenic redox-sensitive probe. Oxidative Medicine and Cellular Longevity. 2021; 2021:6685612. doi: 10.1155/2021/6685612. Impact factor: 7.31.
2. 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: 7.765.
3. Manea SA, Vlad ML, Lazar AG, Muresian H, Simionescu M, Manea A. Lysine-specific histone demethylase 1A contributes to atherosclerotic lesion formation in apolipoprotein E-deficient mice by mediating oxidative stress and inflammation; evidence for implications in human atherosclerosis. Redox Biology, 2022. (Submitted). Impact factor: 10.787.
Oral communications at international meetings:
1. Manea SA, Vlad LM, Mares RG, Lazar AG, Preda BM, Schiopu A, Simionescu M, Manea A. Myeloid cell-derived S100A9 modulates the expression of histone methylation epigenetic enzymes in the myocardium after permanent ischemia in mice. Atherosclerosis. 2021, 331, e34.
2. 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 38th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.
3. 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.
4. 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.
Posters presented at national and international meetings:
1. Vlad LM, Manea SA, Mares RG, Lazar AG, Preda BM, Simionescu M, Schiopu A, Manea A. Pharmacological inhibition of the alarmin S100A9 reduces NADPH oxidase expression and oxidative stress in the infarcted myocardium in mice. Atherosclerosis. 2021, 331, e95-e96.
2. Lazar AG, Vlad LM, Olariu L, Manea SA, Manea A. Triterpenic acids inhibit the expression of inflammation-and oxidative stress-related markers in human pro-inflammatory macrophages. Atherosclerosis. 2021, 331, e79-e80.
3. 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 45th FEBS Congress 2021. FEBS OPEN BIO. 2021, 11, 142.
4. Manea SA, Vlad LM, Lazar AG, Muresian H, Manea A. Inhibition of miR-155-5p reduces NADPH oxidase expression and oxidative stress in the aorta of hypercholesterolemic ApoE-deficient mice: potential implication in human atherosclerosis. FEBS OPEN BIO. 2021, 11, 141-142.
5. 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. 38th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.
6. 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. 38th Annual Scientific Session of the Romanian Society for Cell Biology. 2021.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
Figure 1. The basic principles of the ultrasound-based method for targeted delivery of miRNA inhibitors employing biomimetic microbubbles.
Figure 2. Ultrasound-induced targeted delivery ofmiR-155-5p inhibitor employing VCAM-1-targeted biomimetic microbubbles reduces the expression of NADPH oxidase (a major source of reactive oxygen species production and oxidative stress) isoforms in the atherosclerotic aorta of hypercholesterolemic ApoE-/- mice.
