Dottorato in MEDICINA SPERIMENTALE

Titolo della tesi: ROLE OF MST1 IN THE DEVELOPMENT OF CORONARY ARTERY DISEASE AND ENDOTHELIAL DYSFUNCTION AND MST1-P LEVELS IN PBMC WITH THE PRESENCE AND SEVERITY OF CORONARY ARTERY DISEASE, ENDOTHELIAL DYSFUNCTION, AND OXIDATIVE STRESS

Background and Aim Mammalian sterile 20-like kinase 1 (MST1), a key component of the Hippo signaling pathway, is implicated in the progression of cardiovascular diseases (CVD) through its effects on apoptosis, oxidative stress, and endothelial dysfunction. This study aims to investigate the role of MST1 in the development of coronary artery disease (CAD), endothelial dysfunction, and oxidative stress, exploring its potential as a biomarker and therapeutic target. Materials and Methods The study included both in vitro and in vivo approaches. Endothelial cells were subjected to metabolic stress to evaluate MST1 activation and its downstream effects. MST1-deficient (MST1 eKO) mice were used to examine the preservation of endothelial function under metabolic stress. In human studies, MST1 levels were measured in patients with thoracic and abdominal aortic aneurysms (TAA/AAA) who underwent surgery and in patient affected by coronary artery disease(CAD) who underwent coronary angiography for acute coronary syndrome(ACS), chronic coronary syndrome (CCS) or presence of risk factors predictive for CAD in according to ESC Guidelines. We correlated MST1 levels in PMBC from patient with CAD and no CAD and with disease severity using the SYNTAX score for coronary lesions. Results MST1 activation was significantly induced by metabolic stress in endothelial cells, leading to impaired endothelial function and increased oxidative stress. MST1 eKO mice showed preserved endothelial function and reduced oxidative damage under metabolic stress conditions. In patient studies, elevated MST1 levels correlated with presence of TAA/AA and increased severity of CAD (SYNTAX score), reduced autophagy, and higher oxidative stress markers. These findings support MST1 as a possible CAD biomarker and critical mediator of vascular dysfunction and atherosclerosis. Conclusion MST1 plays a pivotal role in the pathogenesis of CVD by promoting apoptosis, oxidative stress, and endothelial dysfunction. Its inhibition emerges as a promising therapeutic strategy to mitigate cardiovascular damage and improve patient outcomes. This study underscores the potential of MST1 as both a biomarker and a therapeutic target in CVD management.