Kusnierz-Cabala, B. | bioRxiv Science

bioRxiv2024

Mitochondria-targeted hydrogen sulfide donor reduces atherogenesis by reprogramming macrophages and increasing UCP1 expression in vascular smooth muscle cells

AimsAtherosclerosis is a leading cause of morbidity and mortality in the Western countries. A growing body of evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (H2S) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of H2S to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial H2S donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE-/-) mice. ResultsOur results indicated that AP39 reduced atherosclerosis in apoE-/- mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reprogrammed macrophages from proinflammatory M1 to anti-inflammatory M2 in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid {beta}-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE-/- mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation. ConclusionsTaken together, mitochondrial H2S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.

pharmacology and toxicology↗

bioRxiv2024

Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways

BackgroundMetabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem with unmet clinical need. The pathogenesis of MAFLD is very complex including abnormally increased lipogenesis, chronic inflammation, mitochondrial dysfunction, and oxidative stress. A growing body of evidence suggests that hydrogen sulfide (H2S) is an important player in the liver, impacting lipid metabolism and mitochondrial function. However, direct delivery of H2S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. ResultsOur results demonstrated that AP39 reduced fatty liver in HFD-fed mice, which was corresponded with decreased triglyceride content in the liver and plasma as well as increased GSH/GSSG ratio in the plasma. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling in the liver of HFD-fed mice. It also led to a decrease in de novo lipogenesis in the liver by downregulating mTOR/SREBP-1/SCD1 signaling pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of ATGL, a lipolysis enzyme in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of pro inflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to the downregulation of mTOR/NF-{kappa}B signaling pathway. ConclusionsTaken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.

molecular biology↗