Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans
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 <i>PON1</i>-<i&...
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MDPI AG
2020-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/12/1198 |
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| author | Marta Sikora Ewa Bretes Joanna Perła-Kaján Izabela Lewandowska Łukasz Marczak Hieronim Jakubowski |
| author_facet | Marta Sikora Ewa Bretes Joanna Perła-Kaján Izabela Lewandowska Łukasz Marczak Hieronim Jakubowski |
| author_sort | Marta Sikora |
| collection | DOAJ |
| description | 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 <i>PON1</i>-<i>Q192R</i> 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 <i>Pon1</i><sup>−/−</sup> (<i>n</i> = 17) and <i>Pon1</i><sup>+/+</sup> (<i>n</i> = 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. <i>PON1-Q192R</i> polymorphism and <i>Pon1</i><sup>−/−</sup> 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 <i>PON1</i> genotype-dependent proteomic changes affect different biological networks in humans and mice: “cardiovascular, neurological disease, organismal injury/abnormalities” in <i>PON1-192QQ</i> humans and “humoral immune response, inflammatory response, protein synthesis” and “cell-to-cell signaling/interaction, hematological system development/function, immune cell trafficking” in <i>Pon1</i><sup>−/−</sup> 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 <i>PON1</i> genotype can account for its association with cardiovascular and neurological diseases. |
| first_indexed | 2024-03-10T14:29:34Z |
| format | Article |
| id | doaj.art-dd907163f68b4e39a09717b57ba8df9b |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T14:29:34Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-dd907163f68b4e39a09717b57ba8df9b2023-11-20T22:45:20ZengMDPI AGAntioxidants2076-39212020-11-01912119810.3390/antiox9121198Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and HumansMarta Sikora0Ewa Bretes1Joanna Perła-Kaján2Izabela Lewandowska3Łukasz Marczak4Hieronim Jakubowski5European Centre for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, 61-704 Poznań, PolandDepartment of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632 Poznań, PolandDepartment of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632 Poznań, PolandEuropean Centre for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, 61-704 Poznań, PolandEuropean Centre for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, 61-704 Poznań, PolandDepartment of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632 Poznań, PolandHigh-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 <i>PON1</i>-<i>Q192R</i> 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 <i>Pon1</i><sup>−/−</sup> (<i>n</i> = 17) and <i>Pon1</i><sup>+/+</sup> (<i>n</i> = 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. <i>PON1-Q192R</i> polymorphism and <i>Pon1</i><sup>−/−</sup> 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 <i>PON1</i> genotype-dependent proteomic changes affect different biological networks in humans and mice: “cardiovascular, neurological disease, organismal injury/abnormalities” in <i>PON1-192QQ</i> humans and “humoral immune response, inflammatory response, protein synthesis” and “cell-to-cell signaling/interaction, hematological system development/function, immune cell trafficking” in <i>Pon1</i><sup>−/−</sup> 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 <i>PON1</i> genotype can account for its association with cardiovascular and neurological diseases.https://www.mdpi.com/2076-3921/9/12/1198<i>PON1</i> genotypeplasma proteomeslipoproteinsatherosclerosishumansmice |
| spellingShingle | Marta Sikora Ewa Bretes Joanna Perła-Kaján Izabela Lewandowska Łukasz Marczak Hieronim Jakubowski Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans Antioxidants <i>PON1</i> genotype plasma proteomes lipoproteins atherosclerosis humans mice |
| title | Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans |
| title_full | Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans |
| title_fullStr | Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans |
| title_full_unstemmed | Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans |
| title_short | Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans |
| title_sort | genetic attenuation of paraoxonase 1 activity induces proatherogenic changes in plasma proteomes of mice and humans |
| topic | <i>PON1</i> genotype plasma proteomes lipoproteins atherosclerosis humans mice |
| url | https://www.mdpi.com/2076-3921/9/12/1198 |
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