PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction
Background and aimsProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis by regulating low-density lipoprotein (LDL) receptor levels. Despite its known effects on cholesterol metabolism, the role of PCSK9 in cardiac function, especially post-myocardial...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2024.1463844/full |
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| author | Simon Rauterberg Simon Rauterberg Carmen Härdtner Jennifer Hein Paola Schrepf Remi Peyronnet Christoph Koentges Tamara A. Vico Carolin Ehlert Bianca Dufner Diana Lindner Constantin von zur Mühlen Dennis Wolf Dirk Westermann Ingo Hilgendorf Alexander von Ehr |
| author_facet | Simon Rauterberg Simon Rauterberg Carmen Härdtner Jennifer Hein Paola Schrepf Remi Peyronnet Christoph Koentges Tamara A. Vico Carolin Ehlert Bianca Dufner Diana Lindner Constantin von zur Mühlen Dennis Wolf Dirk Westermann Ingo Hilgendorf Alexander von Ehr |
| author_sort | Simon Rauterberg |
| collection | DOAJ |
| description | Background and aimsProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis by regulating low-density lipoprotein (LDL) receptor levels. Despite its known effects on cholesterol metabolism, the role of PCSK9 in cardiac function, especially post-myocardial infarction (MI), remains unclear. This study investigates the impact of PCSK9 on heart function post-MI and evaluates the effects of PCSK9 inhibition via Alirocumab.MethodsWe used PCSK9 knockout (KO) mice and wildtype (WT) mice and in vivo treatment with Alirocumab to analyze cardiac function and survival post-MI induced by permanent ligation of the left anterior descending artery. PCSK9 and LDL receptor levels were measured using ELISA and qRT-PCR. Cardiac function was assessed via echocardiography and isolated working heart model experiments. Gene expression changes were evaluated using RNA sequencing, and inflammatory responses in bone marrow-derived macrophages (BMDMs) were analyzed in vitro.ResultsPCSK9 was expressed in murine heart tissue at levels comparable to the liver, despite minimal heart RNA expression. PCSK9 KO mice had lower plasma cholesterol levels and showed reduced cardiac functions in the working heart model compared to WT mice. Post-MI, PCSK9 KO mice demonstrated significantly improved survival and reduced ventricular rupture compared to WT mice. Alirocumab treatment, while effective in lowering plasma cholesterol, did not replicate the survival benefits seen in PCSK9 KO mice and even worsened cardiac function post-MI. In vitro, PCSK9 induced significant inflammatory responses in macrophages, which were not mitigated by Alirocumab.ConclusionPCSK9 accumulation in the heart post-MI contributes to adverse cardiac remodeling and inflammation. Genetic deletion of PCSK9 confers protection against post-infarct mortality, whereas pharmacological inhibition with Alirocumab fails to reproduce these benefits and may exacerbate cardiac dysfunction. These findings highlight the complex role of PCSK9 in cardiac pathology and caution against the assumption that PCSK9 inhibitors will necessarily yield cardiovascular benefits similar to genetic PCSK9 deficiency. |
| format | Article |
| id | doaj-art-7c6dfd4beef2471286b96b921ea42dbc |
| institution | Kabale University |
| issn | 2297-055X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj-art-7c6dfd4beef2471286b96b921ea42dbc2025-01-21T08:36:53ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2025-01-011110.3389/fcvm.2024.14638441463844PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarctionSimon Rauterberg0Simon Rauterberg1Carmen Härdtner2Jennifer Hein3Paola Schrepf4Remi Peyronnet5Christoph Koentges6Tamara A. Vico7Carolin Ehlert8Bianca Dufner9Diana Lindner10Constantin von zur Mühlen11Dennis Wolf12Dirk Westermann13Ingo Hilgendorf14Alexander von Ehr15Department of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Congenital Heart Disease and Pediatric Cardiology, Faculty of Medicine, University Heart Centre Freiburg—Bad Krozingen, Medical Center—University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyInstitute of Experimental Cardiovascular Medicine, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyInstitute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyDepartment of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, GermanyBackground and aimsProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis by regulating low-density lipoprotein (LDL) receptor levels. Despite its known effects on cholesterol metabolism, the role of PCSK9 in cardiac function, especially post-myocardial infarction (MI), remains unclear. This study investigates the impact of PCSK9 on heart function post-MI and evaluates the effects of PCSK9 inhibition via Alirocumab.MethodsWe used PCSK9 knockout (KO) mice and wildtype (WT) mice and in vivo treatment with Alirocumab to analyze cardiac function and survival post-MI induced by permanent ligation of the left anterior descending artery. PCSK9 and LDL receptor levels were measured using ELISA and qRT-PCR. Cardiac function was assessed via echocardiography and isolated working heart model experiments. Gene expression changes were evaluated using RNA sequencing, and inflammatory responses in bone marrow-derived macrophages (BMDMs) were analyzed in vitro.ResultsPCSK9 was expressed in murine heart tissue at levels comparable to the liver, despite minimal heart RNA expression. PCSK9 KO mice had lower plasma cholesterol levels and showed reduced cardiac functions in the working heart model compared to WT mice. Post-MI, PCSK9 KO mice demonstrated significantly improved survival and reduced ventricular rupture compared to WT mice. Alirocumab treatment, while effective in lowering plasma cholesterol, did not replicate the survival benefits seen in PCSK9 KO mice and even worsened cardiac function post-MI. In vitro, PCSK9 induced significant inflammatory responses in macrophages, which were not mitigated by Alirocumab.ConclusionPCSK9 accumulation in the heart post-MI contributes to adverse cardiac remodeling and inflammation. Genetic deletion of PCSK9 confers protection against post-infarct mortality, whereas pharmacological inhibition with Alirocumab fails to reproduce these benefits and may exacerbate cardiac dysfunction. These findings highlight the complex role of PCSK9 in cardiac pathology and caution against the assumption that PCSK9 inhibitors will necessarily yield cardiovascular benefits similar to genetic PCSK9 deficiency.https://www.frontiersin.org/articles/10.3389/fcvm.2024.1463844/fullPCSK9PCSK9 inhibitorsalirocumabPCSK9 deficiencymyocardial infarctioninflammation |
| spellingShingle | Simon Rauterberg Simon Rauterberg Carmen Härdtner Jennifer Hein Paola Schrepf Remi Peyronnet Christoph Koentges Tamara A. Vico Carolin Ehlert Bianca Dufner Diana Lindner Constantin von zur Mühlen Dennis Wolf Dirk Westermann Ingo Hilgendorf Alexander von Ehr PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction Frontiers in Cardiovascular Medicine PCSK9 PCSK9 inhibitors alirocumab PCSK9 deficiency myocardial infarction inflammation |
| title | PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction |
| title_full | PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction |
| title_fullStr | PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction |
| title_full_unstemmed | PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction |
| title_short | PCSK9-antibodies fail to block PCSK9-induced inflammation in macrophages and cannot recapitulate protective effects of PCSK9-deficiency in experimental myocardial infarction |
| title_sort | pcsk9 antibodies fail to block pcsk9 induced inflammation in macrophages and cannot recapitulate protective effects of pcsk9 deficiency in experimental myocardial infarction |
| topic | PCSK9 PCSK9 inhibitors alirocumab PCSK9 deficiency myocardial infarction inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2024.1463844/full |
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