Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy
Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Using Zincpyr1 staining, we found a significant decrease of intracellular Zinc concentra...
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2021.736911/full |
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| author | Yu Fang Yu Fang Yu Fang Shun Wang Jian Lv Jian Lv Jian Lv Zhenyi Zhao Zhenyi Zhao Ningning Guo Ningning Guo Ningning Guo Gang Wu Jingjing Tong Zhihua Wang Zhihua Wang Zhihua Wang |
| author_facet | Yu Fang Yu Fang Yu Fang Shun Wang Jian Lv Jian Lv Jian Lv Zhenyi Zhao Zhenyi Zhao Ningning Guo Ningning Guo Ningning Guo Gang Wu Jingjing Tong Zhihua Wang Zhihua Wang Zhihua Wang |
| author_sort | Yu Fang |
| collection | DOAJ |
| description | Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Using Zincpyr1 staining, we found a significant decrease of intracellular Zinc concentration in phenylephrine (PE)-induced hypertrophy of neonatal rat ventricular myocytes (NRVMs). We then screened SLC39 family members responsible for zinc uptake and identified Slc39a2 as the only one altered by PE treatment. Slc39a2 knockdown in NRVMs reduced the intracellular Zinc level, and exacerbated the hypertrophic responses to PE treatment. In contrast, adenovirus-mediated Slc39a2 overexpression enhanced zinc uptake and suppressed PE-induced Nppb expression. RNA sequencing analysis showed a pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune signaling pathways, including NOD signaling, TOLL-like receptor, NFκB, and IRFs, were remarkably enriched in the Slc39a2-regulated genes. Slc39a2 deficiency enhanced the phosphorylation of P65 NFκB and STAT3, and reduced the expression of IκBα. Finally, the expression of IRF7 was significantly increased by Slc39a2 knockdown, which was in turn suppressed by IRF7 knockdown. Our data demonstrate that zinc homeostasis mediated by a Slc39a2/IRF7 regulatory circuit contributes to the alteration of innate immune signaling in cardiomyocyte hypertrophy. |
| first_indexed | 2024-04-11T20:06:20Z |
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| language | English |
| last_indexed | 2024-04-11T20:06:20Z |
| publishDate | 2021-11-01 |
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| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-d4096b930abc4377a5e22ba2105d8dcb2022-12-22T04:05:19ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-11-01810.3389/fcvm.2021.736911736911Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte HypertrophyYu Fang0Yu Fang1Yu Fang2Shun Wang3Jian Lv4Jian Lv5Jian Lv6Zhenyi Zhao7Zhenyi Zhao8Ningning Guo9Ningning Guo10Ningning Guo11Gang Wu12Jingjing Tong13Zhihua Wang14Zhihua Wang15Zhihua Wang16Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaShenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, ChinaState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaShenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, ChinaState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaSchool of Pharmacy, Health Science Center, Shenzhen University, Shenzhen, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaShenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, ChinaState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaSchool of Life Sciences, Central China Normal University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaShenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, ChinaState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaZinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Using Zincpyr1 staining, we found a significant decrease of intracellular Zinc concentration in phenylephrine (PE)-induced hypertrophy of neonatal rat ventricular myocytes (NRVMs). We then screened SLC39 family members responsible for zinc uptake and identified Slc39a2 as the only one altered by PE treatment. Slc39a2 knockdown in NRVMs reduced the intracellular Zinc level, and exacerbated the hypertrophic responses to PE treatment. In contrast, adenovirus-mediated Slc39a2 overexpression enhanced zinc uptake and suppressed PE-induced Nppb expression. RNA sequencing analysis showed a pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune signaling pathways, including NOD signaling, TOLL-like receptor, NFκB, and IRFs, were remarkably enriched in the Slc39a2-regulated genes. Slc39a2 deficiency enhanced the phosphorylation of P65 NFκB and STAT3, and reduced the expression of IκBα. Finally, the expression of IRF7 was significantly increased by Slc39a2 knockdown, which was in turn suppressed by IRF7 knockdown. Our data demonstrate that zinc homeostasis mediated by a Slc39a2/IRF7 regulatory circuit contributes to the alteration of innate immune signaling in cardiomyocyte hypertrophy.https://www.frontiersin.org/articles/10.3389/fcvm.2021.736911/fullSLC39A2zinc homeostasiscardiac hypertrophyinnate immune signalingfeedback circuit |
| spellingShingle | Yu Fang Yu Fang Yu Fang Shun Wang Jian Lv Jian Lv Jian Lv Zhenyi Zhao Zhenyi Zhao Ningning Guo Ningning Guo Ningning Guo Gang Wu Jingjing Tong Zhihua Wang Zhihua Wang Zhihua Wang Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy Frontiers in Cardiovascular Medicine SLC39A2 zinc homeostasis cardiac hypertrophy innate immune signaling feedback circuit |
| title | Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy |
| title_full | Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy |
| title_fullStr | Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy |
| title_full_unstemmed | Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy |
| title_short | Slc39a2-Mediated Zinc Homeostasis Modulates Innate Immune Signaling in Phenylephrine-Induced Cardiomyocyte Hypertrophy |
| title_sort | slc39a2 mediated zinc homeostasis modulates innate immune signaling in phenylephrine induced cardiomyocyte hypertrophy |
| topic | SLC39A2 zinc homeostasis cardiac hypertrophy innate immune signaling feedback circuit |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2021.736911/full |
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