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The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis.

ABSTRACT: The incidence and prevalence of cardiovascular diseases are still rising. The principal mechanism that drives them is atherosclerosis, an affection given by dyslipidemia and a pro-inflammatory state. Paraoxonase enzymes have a protective role due to their ability to contribute to antioxidant and anti-inflammatory pathways, especially paraoxonase 1 (PON1). PON1 binds with HDL (high-density lipoprotein), and high serum levels lead to a protective state against dyslipidemia, cardiovascular diseases, diabetes, stroke, nonalcoholic fatty liver disease, and many others. Modulating PON1 expression might be a treatment objective with significant results in limiting the prevalence of atherosclerosis. Lifestyle including diet and exercise can raise its levels, and some beneficial plants have been found to influence PON1 levels; therefore, more studies on herbal components are needed. Our purpose is to highlight the principal roles of Praoxonase 1, its implications in dyslipidemia, cardiovascular diseases, stroke, and other diseases, and to emphasize plants that can modulate PON1 expression, targeting the potential of some flavonoids that could be introduced as supplements in our diet and to validate the hypothesis that flavonoids have any effects regarding PON1 function.

SUBMITTER: Sirca TB

PROVIDER: S-EPMC10931629 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis.

Sirca Teodora Bianca TB Mureșan Mariana Eugenia ME Pallag Annamaria A Marian Eleonora E Jurca Tunde T Vicaș Laura Grațiela LG Tunduc Ioana Paula IP Manole Felicia F Ștefan Liana L

International journal of molecular sciences 20240304 5

The incidence and prevalence of cardiovascular diseases are still rising. The principal mechanism that drives them is atherosclerosis, an affection given by dyslipidemia and a pro-inflammatory state. Paraoxonase enzymes have a protective role due to their ability to contribute to antioxidant and anti-inflammatory pathways, especially paraoxonase 1 (PON1). PON1 binds with HDL (high-density lipoprotein), and high serum levels lead to a protective state against dyslipidemia, cardiovascular diseases ...[more]

PMID: 38474211

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Project description:Diabetes mellitus is a major risk factor for cardiovascular mortality by increasing endothelial cell (EC) dysfunction and subsequently accelerating atherosclerosis. Extracellular-signal regulated kinase 5 (ERK5) is activated by steady laminar flow and regulates EC function by increasing endothelial nitric oxide synthase expression and inhibiting EC inflammation. However, the role and regulatory mechanisms of ERK5 in EC dysfunction and atherosclerosis are poorly understood. Here, we report the critical role of the p90 ribosomal S6 kinase (p90RSK)/ERK5 complex in EC dysfunction in diabetes mellitus and atherosclerosis.Inducible EC-specific ERK5 knockout (ERK5-EKO) mice showed increased leukocyte rolling and impaired vessel reactivity. To examine the role of endothelial ERK5 in atherosclerosis, we used inducible ERK5-EKO-LDLR(-/-) mice and observed increased plaque formation. When activated, p90RSK associated with ERK5, and this association inhibited ERK5 transcriptional activity and upregulated vascular cell adhesion molecule 1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced endothelial nitric oxide synthase expression. p90RSK activity was increased in diabetic mouse vessels, and fluoromethyl ketone-methoxyethylamine, a specific p90RSK inhibitor, ameliorated EC-leukocyte recruitment and diminished vascular reactivity in diabetic mice. Interestingly, in ERK5-EKO mice, increased leukocyte rolling and impaired vessel reactivity were resistant to the beneficial effects of fluoromethyl ketone-methoxyethylamine, suggesting a critical role for endothelial ERK5 in mediating the salutary effects of fluoromethyl ketone-methoxyethylamine on endothelial dysfunction. Fluoromethyl ketone-methoxyethylamine also inhibited atherosclerosis formation in ApoE(-/-) mice.Our study highlights the importance of the p90RSK/ERK5 module as a critical mediator of EC dysfunction in diabetes mellitus and atherosclerosis formation, thus revealing a potential new target for therapeutic intervention.

Dataset Information

The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis.

Publications

The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis.

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