Abstract
Hypertension, diabetes, atherosclerosis and hyperhomocysteinemia are the most common cardiovascular diseases (CVDs) and hardly impact quality of life and health costs. For this reason, the discovery of innovative therapeutic and nutraceutical strategies is compelling. In the last few years, H2S emerged as a fundamental endogenous mediator at cardiovascular level and an impairment of H2S production leads to the onset CVDs. Thus, molecules such as natural polysulfides, isothiocyanates (ITCs) and other sulfur moieties able to donate H2S in an endogenous like manner may be considered an innovative strategy for the pharmacological and nutraceutical treatment of CVDs. Ferroptosis is a newly discovered kind of cell death that takes part in several diseases, including many CVDs, becoming a focus of research for cardiovascular pathologies. Ferroptosis is a regulated and iron-dependent cell death, characterized by iron overloads and lipid peroxidation. Growing evidence demonstrates the beneficial effects of ferroptosis inhibitors (FIs), such as ferrostatin-1 (fer-1) and the iron chelator deferoxamine (DFO) in the protection against CVDs. Although the use of FIs seems to be promising, data regarding their protective activity are limited to preclinical experimental stages and attention must be paid for their chronic use. For instance, chronic use of DFO, approved for the treatment of acute and chronic iron overload, provokes neurotoxicity. Because most of CVDs are chronic states, safer and more effective FIs should be explored. Recent evidence suggests that an impairment in H2S endogenous production induces ferroptosis and, thus, the administration of molecules able to donate H2S may represent an innovative strategy for CVDs prevention, targeting ferroptosis pathway. In this project, the H2S donor properties of selected natural sulfur containing compounds (ITCs-H2S donors) will be tested to check their protective cardiovascular activity and their ability to inhibit ferroptosis. Cell free and cell-based models, represented by human aortic endothelial (HAECs) or smooth muscle cells (HASMCs) will be used. The kinetic of H2S release will be characterized for the selection of the appropriate concentrations of ITCs-H2S donors to achieve cardiovascular protective effects via ferroptosis inhibition. In vitro models of ferroptosis will be set up using different vascular damaging conditions (i.e. high glucose, oxidized low density lipoprotein (ox-LDL), homocysteine) for exploring the actual potential of ferroptosis inhibition by ITCs-H2S donors and for characterizing their mechanism of action. These results will set the basis for the assessment of translational impact of the most promising ITCs-H2S donor in an in vivo CVDs model of atherosclerosis or diabetes.
Dettagli del progetto
Responsabile scientifico: Eleonora Turrini
Strutture Unibo coinvolte:
Dipartimento di Scienze per la Qualità della Vita
Coordinatore:
Università di PISA(Italy)
Contributo totale Unibo: Euro (EUR) 93.947,00
Durata del progetto in mesi: 24
Data di inizio
16/10/2023
Data di fine:
28/02/2026
