RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts
Abstract Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are critical regulators of programmed necrosis or necroptosis. However, the role of the RIPK1/RIPK3 signaling pathway in myocardial fibrosis and related diabetic cardiomyopathy is still unclear. We hypothesized that RIPK1/RIPK3 act...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04587-1 |
| _version_ | 1819279687353892864 |
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| author | Shigang Qiao Lei Hong Yongming Zhu Jun Zha An Wang Jia Qiu Wei Li Chen Wang Jianzhong An Huiling Zhang |
| author_facet | Shigang Qiao Lei Hong Yongming Zhu Jun Zha An Wang Jia Qiu Wei Li Chen Wang Jianzhong An Huiling Zhang |
| author_sort | Shigang Qiao |
| collection | DOAJ |
| description | Abstract Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are critical regulators of programmed necrosis or necroptosis. However, the role of the RIPK1/RIPK3 signaling pathway in myocardial fibrosis and related diabetic cardiomyopathy is still unclear. We hypothesized that RIPK1/RIPK3 activation mediated myocardial fibrosis by impairing the autophagic flux. To this end, we established in vitro and in vivo models of type 2 diabetes mellitus with high glucose fat (HGF) medium and diet respectively. HGF induced myocardial fibrosis, and impaired cardiac diastolic and systolic function by activating the RIPK1/RIPK3 pathway, which increased the expression of autophagic related proteins such as LC3-II, P62 and active-cathepsin D. Inhibition of RIPK1 or RIPK3 alleviated HGF-induced death and fibrosis of cardiac fibroblasts by restoring the impaired autophagic flux. The autophagy blocker neutralized the effects of the RIPK1 inhibitor necrostatin-1 (Nec-1) and RIPK3 inhibitor GSK872 (GSK). RIPK1/RIPK3 inhibition respectively decreased the levels of RIPK3/p-RIPK3 and RIPK1/p-RIPK1. P62 forms a complex with RIPK1-RIPK3 and promotes the binding of RIPK1 and RIPK3, silencing of RIPK1 decreased the association of RIPK1 with P62 and the binding of P62 to LC3. Furthermore, inhibition of both kinases in combination with a low dose of Nec-1 and GSK in the HGF-treated fibroblasts significantly decreased cell death and fibrosis, and restored the autophagic flux. In the diabetic rat model, Nec-1 (1.65 mg/kg) treatment for 4 months markedly alleviated myocardial fibrosis, downregulated autophagic related proteins, and improved cardiac systolic and diastolic function. In conclusion, HGF induces myocardial fibrosis and cardiac dysfunction by activating the RIPK1-RIPK3 pathway and by impairing the autophagic flux, which is obviated by the pharmacological and genetic inhibition of RIPK1/RIPK3. |
| first_indexed | 2024-12-24T00:31:52Z |
| format | Article |
| id | doaj.art-9d672d78ebcc420c903b56b4e72ba66a |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-24T00:31:52Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9d672d78ebcc420c903b56b4e72ba66a2022-12-21T17:24:15ZengNature Publishing GroupCell Death and Disease2041-48892022-02-0113211110.1038/s41419-022-04587-1RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblastsShigang Qiao0Lei Hong1Yongming Zhu2Jun Zha3An Wang4Jia Qiu5Wei Li6Chen Wang7Jianzhong An8Huiling Zhang9Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityInstitute of Clinical Medicine Research, Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityDepartment of Anesthesiology, Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityDepartment of Anesthesiology, Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical UniversityInstitute of Clinical Medicine Research, Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Suzhou Key Laboratory of Drugs Rearch for Prevention and Treatment of Hyperlipidemic Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow UniversityAbstract Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are critical regulators of programmed necrosis or necroptosis. However, the role of the RIPK1/RIPK3 signaling pathway in myocardial fibrosis and related diabetic cardiomyopathy is still unclear. We hypothesized that RIPK1/RIPK3 activation mediated myocardial fibrosis by impairing the autophagic flux. To this end, we established in vitro and in vivo models of type 2 diabetes mellitus with high glucose fat (HGF) medium and diet respectively. HGF induced myocardial fibrosis, and impaired cardiac diastolic and systolic function by activating the RIPK1/RIPK3 pathway, which increased the expression of autophagic related proteins such as LC3-II, P62 and active-cathepsin D. Inhibition of RIPK1 or RIPK3 alleviated HGF-induced death and fibrosis of cardiac fibroblasts by restoring the impaired autophagic flux. The autophagy blocker neutralized the effects of the RIPK1 inhibitor necrostatin-1 (Nec-1) and RIPK3 inhibitor GSK872 (GSK). RIPK1/RIPK3 inhibition respectively decreased the levels of RIPK3/p-RIPK3 and RIPK1/p-RIPK1. P62 forms a complex with RIPK1-RIPK3 and promotes the binding of RIPK1 and RIPK3, silencing of RIPK1 decreased the association of RIPK1 with P62 and the binding of P62 to LC3. Furthermore, inhibition of both kinases in combination with a low dose of Nec-1 and GSK in the HGF-treated fibroblasts significantly decreased cell death and fibrosis, and restored the autophagic flux. In the diabetic rat model, Nec-1 (1.65 mg/kg) treatment for 4 months markedly alleviated myocardial fibrosis, downregulated autophagic related proteins, and improved cardiac systolic and diastolic function. In conclusion, HGF induces myocardial fibrosis and cardiac dysfunction by activating the RIPK1-RIPK3 pathway and by impairing the autophagic flux, which is obviated by the pharmacological and genetic inhibition of RIPK1/RIPK3.https://doi.org/10.1038/s41419-022-04587-1 |
| spellingShingle | Shigang Qiao Lei Hong Yongming Zhu Jun Zha An Wang Jia Qiu Wei Li Chen Wang Jianzhong An Huiling Zhang RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts Cell Death and Disease |
| title | RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| title_full | RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| title_fullStr | RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| title_full_unstemmed | RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| title_short | RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| title_sort | ripk1 ripk3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts |
| url | https://doi.org/10.1038/s41419-022-04587-1 |
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