Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis
Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) p...
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2023-02-01
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| author | Zhongguang Li Qinchun Duan Ying Cui Odell D. Jones Danyang Shao Jianfei Zhang Yuru Gao Xixi Cao Shulin Wang Jiali Li Xinjuan Lei Wei Zhang Liyang Wang Xin Zhou Mengmeng Xu Yingli Liu Jianjie Ma Xuehong Xu |
| author_facet | Zhongguang Li Qinchun Duan Ying Cui Odell D. Jones Danyang Shao Jianfei Zhang Yuru Gao Xixi Cao Shulin Wang Jiali Li Xinjuan Lei Wei Zhang Liyang Wang Xin Zhou Mengmeng Xu Yingli Liu Jianjie Ma Xuehong Xu |
| author_sort | Zhongguang Li |
| collection | DOAJ |
| description | Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction. |
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| spelling | doaj.art-6c9f9927d8344f6bb1b3c0ae3ee135412023-11-16T20:55:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244309410.3390/ijms24043094Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and FerroptosisZhongguang Li0Qinchun Duan1Ying Cui2Odell D. Jones3Danyang Shao4Jianfei Zhang5Yuru Gao6Xixi Cao7Shulin Wang8Jiali Li9Xinjuan Lei10Wei Zhang11Liyang Wang12Xin Zhou13Mengmeng Xu14Yingli Liu15Jianjie Ma16Xuehong Xu17Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaUniversity Laboratory Animal Resources (ULAR), University of Pennsylvania School of Medicine, Philadelphia, PA 19144, USALaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaLaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaDepartment of Pediatrics, Columbia University, New York, NY 10032, USALaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaDepartment of Surgery, Davis Heart and Lung Research Institute, Ohio State University School of Medicine, Columbus, OH 43210, USALaboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi’an 710062, ChinaTransgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.https://www.mdpi.com/1422-0067/24/4/3094cardiac-specific Creheart failureatrial tumorsmatrix metalloproteinasescalcium channelmyocardial intercalated discs |
| spellingShingle | Zhongguang Li Qinchun Duan Ying Cui Odell D. Jones Danyang Shao Jianfei Zhang Yuru Gao Xixi Cao Shulin Wang Jiali Li Xinjuan Lei Wei Zhang Liyang Wang Xin Zhou Mengmeng Xu Yingli Liu Jianjie Ma Xuehong Xu Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis International Journal of Molecular Sciences cardiac-specific Cre heart failure atrial tumors matrix metalloproteinases calcium channel myocardial intercalated discs |
| title | Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis |
| title_full | Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis |
| title_fullStr | Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis |
| title_full_unstemmed | Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis |
| title_short | Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis |
| title_sort | cardiac specific expression of cre recombinase leads to age related cardiac dysfunction associated with tumor like growth of atrial cardiomyocyte and ventricular fibrosis and ferroptosis |
| topic | cardiac-specific Cre heart failure atrial tumors matrix metalloproteinases calcium channel myocardial intercalated discs |
| url | https://www.mdpi.com/1422-0067/24/4/3094 |
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