Changes in redox plasma proteome of Pon1−/− mice are exacerbated by a hyperhomocysteinemic diet

Sikora, Marta; Jakubowski, Hieronim

doi:10.1016/j.freeradbiomed.2021.03.042

Cited by 6 publications

(5 citation statements)

References 62 publications

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“…In mice, Pon1 protects from atherosclerosis induced by a high-fat diet [84] or ApoE depletion [85]. Cardio protection by PON1 can be due to its apparent antioxidative function mediated by interactions of PON1 with redox response-related proteins [86,87] and its ability to detoxify Hcy-thiolactone [24,52,88], which attenuate lipid/protein peroxidation [79,84,89], and protein N-homocysteinylation [29,52,69]. PON1 has also been implicated in AD [90][91][92], which may not be unexpected given that AD has a significant vascular component [93].…”

Section: Paraoxonasementioning

confidence: 99%

Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease

Jakubowski

2024

Preprint

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Elevated levels of homocysteine (Hcy) and related metabolites are associated with Alzheimer’s disease (AD). Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, and thus is a non-protein amino acid, it can be attached to proteins via an N-homocysteinylation reaction mediated by Hcy-thiolactone. Because N-homocysteinylation is detrimental to protein’s function and biological integrity, Hcy-thiolactone detoxifying enzymes – PON1, BLMH, BPHL – have evolved. This review provides an account of the biological function of these enzymes and of consequences of their impairments leading to phenotypes characteristic of AD.

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Section: Paraoxonasementioning

confidence: 99%

Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease

Jakubowski

2024

Preprint

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“…In addition to elevated Hcy, HHcy is characterized by elevated levels of Hcy-thiolactone and N -Hcy-protein, observed in nutritional or genetic deficiencies in Hcy metabolism in animals and humans 7 . HHcy is also characterized by pro-atherogenic changes in gene expression in mice and humans 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, miR-216-5p, and miR-320c-3p in human vascular endothelial cells

Witucki,

Jakubowski

2024

Sci Rep

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Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired autophagy causes the accumulation of damaged proteins and organelles and is associated with CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of Hcy-thiolactone, N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein levels. We also found that these changes were mediated by upregulation by Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then downregulate autophagy in human endothelial cells, important for vascular homeostasis.

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“…Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites such as Hcy-thiolactone and N -Hcy-protein, seen in genetic and nutritional deficiencies in Hcy metabolism in humans and animals (8). Genetically or nutritionally induced HHcy causes pro-atherogenic changes in gene expression in mice and humans (9, 10).…”

Section: Introductionmentioning

confidence: 99%

Homocysteine Metabolites Impair the Phf8/H4K20me1/mTOR/Autophagy Pathway by Upregulating the Expression of PHF8-targeting miR-22-3p and miR-1229-3p in Human Vascular Endothelial Cells

Witucki

Jakubowski

2023

Preprint

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The inability to efficiently metabolize homocysteine (Hcy), which occurs in nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) thereby causing endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). The dysregulation of mammalian target of rapamycin (mTOR) signaling, and impaired autophagy play important roles in CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone (HTL) and N-Hcy-protein (N-Hcy). However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of HTL, N-Hcy, and Hcy on the PHF8/H4K20me1/mTOR/autophagy pathway in human umbilical vein endothelial cells (HUVEC). We found that treatments with HTL, N-Hcy, or Hcy significantly reduced PHF8 protein and mRNA expression, increased H4K20me1, and upregulated mTOR signaling. Autophagy was also impaired (significantly downregulated BECN1, ATG5, ATG7, and LC3 protein and mRNA levels). We also found that these changes were mediated by PHF8-targeting microRNA (miR): miR-22-3p and miR-1229-3p. The effects of HTL, N-Hcy, or Hcy on the miR expression and on the PHF8/H4K20me1/mTOR/autophagy pathway were abrogated by treatments with an inhibitor of miR-22 or miR-1229. Taken together, these findings show that Hcy metabolites can upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.

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Changes in redox plasma proteome of Pon1−/− mice are exacerbated by a hyperhomocysteinemic diet

Cited by 6 publications

References 62 publications

Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease

Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease

Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, miR-216-5p, and miR-320c-3p in human vascular endothelial cells

Homocysteine Metabolites Impair the Phf8/H4K20me1/mTOR/Autophagy Pathway by Upregulating the Expression of PHF8-targeting miR-22-3p and miR-1229-3p in Human Vascular Endothelial Cells

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