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 is a major contributor to the development and progression of atherosclerosis, yet the molecular mechanisms linking vascular senescence to plaque instability and thrombotic risk remain incompletely understood. This task aimed to investigate the molecular pathways driving vascular senescence, with particular emphasis on the cross-talk between telomere dysfunction and mitochondrial alterations, to identify potential therapeutic targets and novel diagnostic or prognostic biomarkers for acute coronary syndrome.
To address this objective, we employed replicative and stress-induced senescence models in human vascular cells and analyzed well-characterized patient cohorts covering the clinical spectrum of angina pectoris (stable angina, unstable angina, NSTEMI, and STEMI). In addition, a MAPK15 knockout mouse model was used to investigate the role of this kinase in vascular aging and cardiometabolic disease. Specific aims:
1. In vitro studies on vascular cell senescence
Telomeric and mitochondrial alterations were investigated in human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (hVSMCs) undergoing replicative senescence (RS) or stress-induced premature senescence (SIPS), induced by exposure to fine dust (FD; 50–100 µg/ml). The protective effects of astragaloside IV (AS-IV; 50 µM) were also evaluated.
2. Role of MAPK15 in cellular response to oxidative stress and in metabolic liver disease
Using a MAPK15 knockout mouse model, we investigated its role in hepatic lipid homeostasis and metabolically associated steatotic liver disease (MASLD). Mapk15−/− mice developed hepatic steatosis consistent with a MASLD-like phenotype.
3. Clinical studies in coronary artery disease
A clinical investigation (ClinicalTrials.gov identifier: NCT063136; Vascular Senescence and Atherosclerotic Plaque Vulnerability – VICTORIA) enrolled more than 400 patients undergoing coronary angiography, resulting in the collection of over 2,000 biological samples. Peripheral blood samples were analyzed in three groups: patients with acute coronary syndrome (STEMI, NSTEMI, unstable angina), patients with stable angina, and patients with normal coronary arteries.
The main findings are summarized below.
1. In vitro studies on vascular cell senescence
Results showed that vascular senescence involves cell type–specific telomere–mitochondria interactions modulated by environmental stressors. Endothelial cells were particularly susceptible to pollution-induced senescence, whereas vascular smooth muscle cells displayed weaker or alternative responses. AS-IV selectively protected endothelial cells, supporting the potential of telomere-targeted interventions to delay vascular aging. These findings were presented at the 2nd Age-IT General Meeting (Naples, October 29–31, 2025), and a manuscript has been submitted for publication.
2. Role of MAPK15 in cellular response to oxidative stress and in metabolic liver disease
In vitro studies demonstrated that the atypical MAP kinase MAPK15 regulates mitophagy, promotes cytoprotective responses to reactive oxygen species, prevents excessive DNA damage, and limits activation of the cellular senescence phenotype. In vivo hepatocellular models showed that lipid accumulation was associated with increased expression and membrane localization of the fatty acid translocase CD36. Consistently, Mapk15−/− mice exhibited elevated hepatic CD36 levels, and a Western-type high-fat diet accelerated progression toward a steatohepatitis-like phenotype. (DOI: 10.1097/HC9.0000000000000870).
3. Clinical studies in coronary artery disease
Results indicated that mitochondrial dysfunction, together with traditional cardiovascular risk factors, contributes to early-onset coronary artery disease (DOI: 10.3389/fcvm.2025.1538202). An additional study evaluated the effects of air pollution on mitochondrial function. Short-term exposure to PM2.5 and PM10 was associated with reduced mitochondrial DNA copy number (mtDNAcn) in ACS patients. Moreover, mtDNAcn was negatively correlated with inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII). These findings suggest that oxidative stress and inflammation may induce mitochondrial dysfunction, potentially contributing to plaque vulnerability and acute cardiovascular events (DOI: 10.1093/eurheartj/ehaf784.1895). Finally, we investigated the relationship between leukocyte telomere length, telomeric repeat-containing RNA (TERRA), and senescence markers (p21Cip1 and p16Ink4a) in patients with ACS and stable angina. Altered expression of TERRA and senescence markers was observed in ACS patients, highlighting telomere-associated pathways as potential contributors to plaque destabilization and possible therapeutic targets (DOI: 10.1093/eurheartj/ehaf784.1861).
Total number of publications and scientific contributions acknowledging the grant.