Leader: Maria Grazia Andreassi (IFC-CNR, Pisa); Other collaborator(s): Mario Chiariello (IFC-CNR, Siena), Jonica Campolo (IFC-CNR, MIlano), Giuseppina Basta (IFC-CNR, Pisa)
Vascular aging plays a key role in the development of atherosclerosis, yet the molecular mechanisms influencing plaque stability and increasing the risk of thrombotic complications remain poorly understood. This project aims to comprehensively investigate the molecular pathways driving vascular senescence, with a particular focus on telomere-mitochondria cross-talk, to identify potential therapeutic targets and novel diagnostic or prognostic markers in acute coronary syndrome.
To achieve this, we will utilize replicative and stress-induced models of human vascular cellular senescence, along with well-characterized patient cohorts spanning the spectrum of angina pectoris (stable angina, unstable angina, NSTEMI, and STEMI). In addition, we will use a MAPK15 knockout mouse model to study the role of this kinase in vascular aging and cardiometabolic disease.
The project is progressing well, with several research activities completed:
- Cell Senescence in vitro studies: Investigated telomeric and mitochondrial biology in human umbilical vein endothelial cells (HUVECs) using replicative and stress-induced premature senescence (SIPS) models. Findings suggest similarities between these two types of senescence.
- MAPK15 and Liver Disease: Using a MAPK15 knockout mouse model, we explored its protective role against liver steatosis and metabolically induced steatotic liver disease (MASLD). Results indicate that MAPK15 helps mitigate the harmful effects of cardiometabolic risk factors, suggesting its potential for therapeutic targeting.
- Clinical Study on Coronary Artery Disease: Enrolled 176 patients undergoing coronary angiography and collected over 1,500 biological samples. Preliminary findings link premature coronary artery disease to modifiable risk factors and mitochondrial damage, pointing to the potential of mitochondrial-targeted therapies.
To date, 7 papers have been published with an acknowledgment of the grant received:
- Borghini, Andrea, Rudina Ndreu, Paola Canale, Jonica Campolo, Irene Marinaro, Antonella Mercuri, Stefano Turchi, and Maria Grazia Andreassi. 2024. "Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells" International Journal of Molecular Sciences 25, no. 3: 1428. https://doi.org/10.3390/ijms25031428
- Canale P, Campolo J, Borghini A, Andreassi MG. Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease. Biomedicines. 2023 Dec 3;11(12):3211. doi: 10.3390/biomedicines11123211.
- Franci L, Vallini G, Bertolino FM, Cicaloni V, Inzalaco G, Cicogni M, Tinti L, Calabrese L, Barone V, Salvini L, Rubegni P, Galvagni F, Chiariello M. MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes. Redox Biol. 2024 Jun;72:103131. doi: 10.1016/j.redox.2024.103131. Epub 2024 Mar 28. PMID: 38555711; PMCID: PMC10998232.
- Campolo J, Canale P, Piccaluga E, Bossi I, Gazzaniga G, Parolini M, et al. Vascular senescence and atherosclerotic plaque vulnerability: investigating the telomere-mitochondria crosstalk—rationale and design of the VICTORIA Study. Explor Cardiol. 2024;2:168–77. https://doi.org/10.37349/ec.2024.00030
- Gargiulo, S.; Barone, V.; Bonente, D.; Tamborrino, T.; Inzalaco, G.; Gherardini, L.; Bertelli, E.; Chiariello, M. Integrated Ultrasound Characterization of the Diet-Induced Obesity (DIO) Model in Young Adult c57bl/6j Mice: Assessment of Cardiovascular, Renal and Hepatic Changes. J. Imaging 2024, 10, 217.
- Russo, Lara, Serena Babboni, Maria Grazia Andreassi, Jalil Daher, Paola Canale, Serena Del Turco, and Giuseppina Basta. 2025. "Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?" Antioxidants 14, no. 1: 99. https://doi.org/10.3390/antiox14010099
- Campolo J, Canale P, Gazzaniga G, Parolini M, Piccaluga E, Bossi I, Oreglia J, Borghini A, Marinaro I, Andreassi MG. The mitochondrial dysfunction, alongside the modifiable burden of traditional risk factors, drives the development of early-onset coronary artery disease. Front Cardiovasc Med. 2025 Feb 19;12:1538202. doi: 10.3389/fcvm.2025.1538202. PMID: 40046962; PMCID: PMC11880287.