Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2
Abstract High serum level of palmitic acid(PA) is implicated in pathogenesis of cardiovascular diseases. PA serves as the substrate for protein palmitoylation. However, it is still unknown whether palmitoylation is involved in PA‐induced cardiovascular dysfunction. Here, in clinical cohort studies o...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202412895 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540890444333056 |
|---|---|
| author | Yu He Senlin Li Lujing Jiang Kejue Wu Shanshan Chen Linjie Su Cui Liu Peiqing Liu Wenwei Luo Shilong Zhong Zhuoming Li |
| author_facet | Yu He Senlin Li Lujing Jiang Kejue Wu Shanshan Chen Linjie Su Cui Liu Peiqing Liu Wenwei Luo Shilong Zhong Zhuoming Li |
| author_sort | Yu He |
| collection | DOAJ |
| description | Abstract High serum level of palmitic acid(PA) is implicated in pathogenesis of cardiovascular diseases. PA serves as the substrate for protein palmitoylation. However, it is still unknown whether palmitoylation is involved in PA‐induced cardiovascular dysfunction. Here, in clinical cohort studies of 1040 patients with coronary heart disease, high level of PA is associated with risk of major adverse cardiovascular events (MACE) and death. In ApoE−/−mice, 10 mg/kg−1 PA treatment induces blood pressure elevation, cardiac contractile dysfunction, endothelial dysfunction and atherosclerotic plaqueformation. In endothelial cells, inhibition of palmitoylation bypalmitoyl‐transferase inhibitor 2‐BP eliminates PA‐induced endothelial injury, whereas promotion of palmitoylation by depalmitoylase inhibitor ML349 exacerbates the harmful effect of PA. Palmitoyl‐proteomics analysis identifies pyruvate kinase isozyme type M2 (PKM2) as the palmitoylated protein responsible for PA‐induced endothelial injury, and Cys31 as the predominant palmitoylated site. PKM2‐C31S mutants (cysteine replaced by serine) prevents PA‐induced endothelial injury. Endothelial‐specific AAV‐C31S PKM2endo ameliorates cardiovascular dysfunction caused by PA in ApoE−/− mice. Mechanistically, PKM2‐C31 palmitoylation impairs PKM2 tetramerization to inhibit its pyruvate kinase activity and endothelial glycolysis. Finally, zDHHC13 is identified as the palmitoyl acyltransferase of PKM2. In conclusion, these findings suggest that PKM2‐C31 palmitoylation contributes to PA‐induced endothelial injury and cardiovascular dysfunction. |
| format | Article |
| id | doaj-art-46235a72b55c42ec964c34263b981fd1 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-46235a72b55c42ec964c34263b981fd12025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202412895Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2Yu He0Senlin Li1Lujing Jiang2Kejue Wu3Shanshan Chen4Linjie Su5Cui Liu6Peiqing Liu7Wenwei Luo8Shilong Zhong9Zhuoming Li10Department of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacy Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaDepartment of Pharmacy Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 P. R. ChinaDepartment of Pharmacy Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 P. R. ChinaDepartment of Pharmacology and Toxicology School of Pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs Evaluation Guangdong Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat‐sen University Guangzhou 510006 P. R. ChinaAbstract High serum level of palmitic acid(PA) is implicated in pathogenesis of cardiovascular diseases. PA serves as the substrate for protein palmitoylation. However, it is still unknown whether palmitoylation is involved in PA‐induced cardiovascular dysfunction. Here, in clinical cohort studies of 1040 patients with coronary heart disease, high level of PA is associated with risk of major adverse cardiovascular events (MACE) and death. In ApoE−/−mice, 10 mg/kg−1 PA treatment induces blood pressure elevation, cardiac contractile dysfunction, endothelial dysfunction and atherosclerotic plaqueformation. In endothelial cells, inhibition of palmitoylation bypalmitoyl‐transferase inhibitor 2‐BP eliminates PA‐induced endothelial injury, whereas promotion of palmitoylation by depalmitoylase inhibitor ML349 exacerbates the harmful effect of PA. Palmitoyl‐proteomics analysis identifies pyruvate kinase isozyme type M2 (PKM2) as the palmitoylated protein responsible for PA‐induced endothelial injury, and Cys31 as the predominant palmitoylated site. PKM2‐C31S mutants (cysteine replaced by serine) prevents PA‐induced endothelial injury. Endothelial‐specific AAV‐C31S PKM2endo ameliorates cardiovascular dysfunction caused by PA in ApoE−/− mice. Mechanistically, PKM2‐C31 palmitoylation impairs PKM2 tetramerization to inhibit its pyruvate kinase activity and endothelial glycolysis. Finally, zDHHC13 is identified as the palmitoyl acyltransferase of PKM2. In conclusion, these findings suggest that PKM2‐C31 palmitoylation contributes to PA‐induced endothelial injury and cardiovascular dysfunction.https://doi.org/10.1002/advs.202412895cardiovascular dysfunctionendothelial injurypalmitic acidpalmitoylationPKM2 |
| spellingShingle | Yu He Senlin Li Lujing Jiang Kejue Wu Shanshan Chen Linjie Su Cui Liu Peiqing Liu Wenwei Luo Shilong Zhong Zhuoming Li Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 Advanced Science cardiovascular dysfunction endothelial injury palmitic acid palmitoylation PKM2 |
| title | Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 |
| title_full | Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 |
| title_fullStr | Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 |
| title_full_unstemmed | Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 |
| title_short | Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2 |
| title_sort | palmitic acid accelerates endothelial cell injury and cardiovascular dysfunction via palmitoylation of pkm2 |
| topic | cardiovascular dysfunction endothelial injury palmitic acid palmitoylation PKM2 |
| url | https://doi.org/10.1002/advs.202412895 |
| work_keys_str_mv | AT yuhe palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT senlinli palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT lujingjiang palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT kejuewu palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT shanshanchen palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT linjiesu palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT cuiliu palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT peiqingliu palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT wenweiluo palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT shilongzhong palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 AT zhuomingli palmiticacidacceleratesendothelialcellinjuryandcardiovasculardysfunctionviapalmitoylationofpkm2 |