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: Human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) were treated with fine dust (FD; 50 and 100 µg/ml) to induce oxidative stress and treated with Astragaloside IV (AS-IV; 50 µM) to investigate telomere dynamics. In vitro, cellular stress was shown to accelerate telomere dysfunction, an effect that was mitigated by AS-IV treatment. The results will be presented at the 2ND GENERAL MEETING Age-IT, Napoli, 29-30-31 Ottobre 2025.
MAPK15 and Liver Disease: The first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) was characterized, revealing a critical role for this protein in controlling lipid homeostasis in the liver. Indeed, Mapk15-/- mice exhibited liver steatosis in the context of a MASLD-like phenotype, while hepatocellular in vitro models allowed to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type high-fat diet significantly accelerated their progression to a steatohepatitis-like phenotype. Importantly, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, suggesting a compensatory role in disease progression. In this context, overexpression of this kinase efficiently opposed lipid accumulation in a MASLD hepatocellular model, opening the possibility of counteracting hepatic steatosis in humans by pharmacologically or genetically activating this MAP kinase. The manuscript was submitted to Hepatology Communications.
Clinical Study on Coronary Artery Disease: To date, we have enrolled 240 patients undergoing coronary angiography, and we have collected over 2,000 biological samples. Peripheral blood samples were analyzed from three patient groups undergoing coronary angiography: 98 patients with acute coronary syndrome (ACS), including cases of ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina; 87 patients with stable angina; and 39 patients with normal coronary arteries. Leukocyte telomere length (LTL), telomeric repeat-containing RNA (TERRA), and markers of cellular senescence (p16INK4a and p21Cip1) were quantified using qPCR. The results revealed a significant association between reduced LTL, altered expression of TERRA, and increased cellular senescence markers in ACS patients. The results will be presented at the ESC Congress 2025, hosted by the European Society of Cardiology ESC ), from 29 August to 1 September 2025 in Madrid, Spain.
OUTPUTS
To date, 8 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.
Taranta M, Panepinto S, Galvagni F, Franci L, Chiariello M. MAPK15 Prevents IFNB1 Expression by Suppressing Oxidative Stress-Dependent Activation of the JNK-JUN Pathway. Int J Mol Sci. 2025 May 27;26(11):5148. doi: 10.3390/ijms26115148.