Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans

Abstract

High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-inflammatory, antioxidative, and antithrombotic activities. Paraoxonase 1 (PON1), carried on HDL in the blood, can contribute to these antiatherogenic activities. The PON1-Q192R polymorphism involves a change from glutamine (Q variant) to arginine (R variant) at position 192 of the PON1 protein and affects its enzymatic activity. The molecular basis of PON1 association with cardiovascular and neurological diseases is not fully understood. To get insight into the function of PON1 in human disease, we examined how genetic attenuation of PON1 levels/activity affect plasma proteomes of mice and humans. Healthy participants (48.9 years old, 50% women) were randomly recruited from the Poznań population. Four-month-old Pon1−/− (n = 17) and Pon1+/+ (n = 8) mice (50% female) were used in these experiments. Plasma proteomes were analyzed using label-free mass spectrometry. Bioinformatics analysis was carried out using the Ingenuity Pathway Analysis (IPA) resources. PON1-Q192R polymorphism and Pon1−/− genotype induced similar changes in plasma proteomes of humans and mice, respectively. The top molecular network, identified by IPA, affected by these changes involved proteins participating in lipoprotein metabolism. Other PON1 genotype-dependent proteomic changes affect different biological networks in humans and mice: “cardiovascular, neurological disease, organismal injury/abnormalities” in PON1-192QQ humans and “humoral immune response, inflammatory response, protein synthesis” and “cell-to-cell signaling/interaction, hematological system development/function, immune cell trafficking” in Pon1−/− mice. Our findings suggest that PON1 interacts with molecular pathways involved in lipoprotein metabolism, acute/inflammatory response, and complement/blood coagulation that are essential for blood homeostasis. Modulation of those interactions by the PON1 genotype can account for its association with cardiovascular and neurological diseases.

Paraoxonase 1 gene polymorphisms in lipid oxidation and atherosclerosis development

“…Both findings suggest a proatherogenic proteomic shift by reducing PON1 levels. The PON1-192QQ genotype was associated with downregulation of F13B and SERPINA1, both involved in the coagulation process, thus increasing the risk of atherothrombosis (Sikora et al, 2020). Serum PON1 concentrations in the general population show very high variability.…”

“…One of the most studied PON1 nucleotide change is the rs622 (c.575A > G) missense mutation, which leads to a glutamine -arginine replacement at position 192 (p.Gln192Arg). This mutation leads to increased paraoxonase activity (Sikora et al, 2020). rs854560 (c.163A > T) is a missense mutation that results in the replacement of leucine with methionine at position 55 (p.Leu55Met).…”

On the Role of Paraoxonase-1 and Chemokine Ligand 2 (C-C motif) in Metabolic Alterations Linked to Inflammation and Disease. A 2021 Update

“…PON1 also promotes the differentiation of macrophages into an anti-inflammatory phenotype [146]. An interesting study [147] demonstrated that genetically reduced PON1 concentration induces proatherogenic changes in plasma proteomes in humans and mice. The study investigated the influence of the least efficient isoforms of PON1 genetic polymorphisms in humans and Pon1−/− genotype in mice and found that both genetic modifications induce changes in the plasma proteome that affect biological networks involving proteins participating in lipoprotein metabolism, in CVD in neurological diseases, in immune response, inflammatory response, in cell-to-cell signaling, and immune-cell trafficking.…”

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

“…PON1 also promotes the differentiation of macrophages into an anti-inflammatory phenotype [146]. A recent study of note [147] showed that genetically reduced PON1 concentration induces proatherogenic changes in plasma proteomes in humans and mice. The study investigated the influence of the least efficient isoforms of PON1 genetic polymorphisms in humans and Pon1−/− genotype in mice and found that both genetic modifications induce changes in the plasma proteome that affect biological networks involving proteins participating in lipoprotein metabolism, in CVD in neurological diseases, in immune response, inflammatory response, in cell-to-cell signaling and immune-cell trafficking.…”