Assessment of the effects of hydrogen sulfide (H2S) donors on the proliferation and migration of cultured vascular endothelial and smooth muscle cells.

• Grant number: 24/01203-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2024
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Marcelo Nicolas Muscara
• Grantee: Sophia Maria Machado da Veiga
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The scientific literature of the last quarter of a century reports the vascular effects of the endogenous mediator hydrogen sulfide (H2S) and its donor compounds, which, in addition to to the antioxidant, anti-inflammatory and stimulating effects of mitochondrial function, make H2S and its donors compounds with relevant therapeutic potential for the treatment of vascular diseases. In particular, in the case of selective H2S donors for mitochondria (such as the compound AP39), their antioxidant activity in cultured endothelial cells subjected to oxidative stress has already been described, as well as their beneficial in vivo effects on myocardial ischemia-reperfusion and vasodilation, and in vitro vasorelaxation. Another class of H2S donors comprises hybrid compounds synthesized from non-steroidal anti-inflammatory drugs (NSAIDs) linked to a radical capable of releasing H2S. One of these molecules, the compound ATB-346 (otenaproxesul"; Antibe Therapeutics Ltd., Canada), in addition to showing a more potent anti-inflammatory effect than the parent compound, also has protective effects, such as inducing apoptosis of leukocytes in vitro and, mainly, the absence of gastric effects, the main adverse effect of NSAIDs, both in animals and humans. In a previous work from our laboratory, we have demonstrated the in vitro vasorelaxant activity of H2S donors (e.g., AP39, NaHS, etc.) using mouse mesenteric artery rings, which involves (to a greater or lesser extent, depending on the type of donor) both direct effects of H2S on smooth muscles and the participation of the endothelium. However, there is no consensus regarding the mechanisms involving H2S in the proliferation and migration of vascular cells. It should be noted that such processes are essential for angiogenesis and tissue regeneration, in addition to influencing the severity of certain clinical situations, such as myocardial hypertrophy. In this way, the general objective of the present project is to investigate the effects of H2S donors (in particular, mitochondrial and those derived from NSAIDs) on endothelial and vascular smooth muscle proliferation in culture, as well as the underlying signaling mechanisms. Among the mechanisms, those involving endothelial NO production, potassium channels and mitochondrial function will be firstly investigated, without prejudice to other potential targets (such as prostaglandins, calcium channels, growth factors, etc.).