Dottorato in SCIENZE DELLA VITA

Titolo della tesi: Role of OPA1 in endothelial dysfunction

Cardiovascular diseases (CVDs) are the leading cause of death in the world and one of the most important public health problems, being also among the main causes of comorbidity and disability. The role of endothelium in vascular health is well-known, and its dysfunction is associated with cardiovascular disorders. Emerging evidence demonstrated that defects of mitochondrial dynamics are associated with the onset and development of several cardiac diseases, making mitochondrial dynamics a potential therapeutic target. Optic Atrophy 1 (OPA1) regulates mitochondrial fusion and exerts cardioprotective effects. However, the role of OPA1 in endothelial cells in response to cardiovascular stress is completely unknown. This study investigated the effects of OPA1 modulation in endothelial cells undergoing treatment with common cardiovascular risk factors. Human umbilical vein endothelial cells (HUVECs) were exposed to conditions mimicking type 2 diabetes (high glucose, HG 30mM), hypercholesterolemia (oxidised LDL, ox-LDL 30μg/ml), and smoking (cigarette smoke condensate, CSC 20 μg/ml). OPA1 levels, mitochondrial network, mitochondrial activity, nitric oxide (NO) production, oxidative stress and angiogenesis were evaluated in these conditions, in the presence or the absence of OPA1 gene silencing or OPA1 overexpression. The effects of OPA1 overexpression were also evaluated on endothelial-dependent vasorelaxation in isolated arteries from mice subjected to stress ex vivo. I demonstrated that short-time exposure to cardiovascular stressors increases OPA1 levels in endothelial cells affecting mitochondrial dynamics and function. OPA1 gene silencing exacerbates stress-induced endothelial dysfunction whereas OPA1 overexpression rescues it. My results suggest that OPA1 may be considered an interesting therapeutic target for the reduction of CVDs in individuals at high risk, such as smokers, and patients with diabetes, obesity or metabolic syndrome.