Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms
Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiat...
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MDPI AG
2023-07-01
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| author | Loretta Lazzarato Laura Bianchi Annapaola Andolfo Agnese Granata Matteo Lombardi Matteo Sinelli Barbara Rolando Marina Carini Alberto Corsini Roberta Fruttero Lorenzo Arnaboldi |
| author_facet | Loretta Lazzarato Laura Bianchi Annapaola Andolfo Agnese Granata Matteo Lombardi Matteo Sinelli Barbara Rolando Marina Carini Alberto Corsini Roberta Fruttero Lorenzo Arnaboldi |
| author_sort | Loretta Lazzarato |
| collection | DOAJ |
| description | Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans’ inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules. |
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| spelling | doaj.art-5242d759d14f4a8884041774b0f83b092023-11-18T23:18:03ZengMDPI AGMolecules1420-30492023-07-012815572410.3390/molecules28155724Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent MechanismsLoretta Lazzarato0Laura Bianchi1Annapaola Andolfo2Agnese Granata3Matteo Lombardi4Matteo Sinelli5Barbara Rolando6Marina Carini7Alberto Corsini8Roberta Fruttero9Lorenzo Arnaboldi10Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, ItalyFunctional Proteomics Laboratory, Department of Life Sciences, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyProteomics and Metabolomics Facility (ProMeFa), Center for Omics Sciences (COSR), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, ItalyDepartment of Pharmaceutical Sciences “Pietro Pratesi”, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, ItalyDepartment of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyPhysiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans’ inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules.https://www.mdpi.com/1420-3049/28/15/5724atherosclerosissmooth muscle cell proliferationnitric oxidefuroxanssmall ubiquitin-related modifier 1proteomics |
| spellingShingle | Loretta Lazzarato Laura Bianchi Annapaola Andolfo Agnese Granata Matteo Lombardi Matteo Sinelli Barbara Rolando Marina Carini Alberto Corsini Roberta Fruttero Lorenzo Arnaboldi Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms Molecules atherosclerosis smooth muscle cell proliferation nitric oxide furoxans small ubiquitin-related modifier 1 proteomics |
| title | Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms |
| title_full | Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms |
| title_fullStr | Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms |
| title_full_unstemmed | Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms |
| title_short | Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms |
| title_sort | proteomics studies suggest that nitric oxide donor furoxans inhibit in vitro vascular smooth muscle cell proliferation by nitric oxide independent mechanisms |
| topic | atherosclerosis smooth muscle cell proliferation nitric oxide furoxans small ubiquitin-related modifier 1 proteomics |
| url | https://www.mdpi.com/1420-3049/28/15/5724 |
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