Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy
After a myocardial infarction (MI), an increase in the cardiac ratio of matrix metalloproteinases (MMPs) relative to their inhibitors (TIMPs) causes extracellular matrix modulation that leads to ventricular dilatation and congestive heart failure. Cell therapy can mitigate these effects. In this stu...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2012-05-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368911X601000 |
| _version_ | 1818318422445916160 |
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| author | Hai Tian M.D., Ph.D. Ming-Li Huang Kai-Yu Liu Zhi-Bo Jia Lu Sun Shu-Lin Jiang Wei Liu Heather Y. Mcdonald Kinkaid Jun Wu Ren-Ke Li M.D., Ph.D. |
| author_facet | Hai Tian M.D., Ph.D. Ming-Li Huang Kai-Yu Liu Zhi-Bo Jia Lu Sun Shu-Lin Jiang Wei Liu Heather Y. Mcdonald Kinkaid Jun Wu Ren-Ke Li M.D., Ph.D. |
| author_sort | Hai Tian M.D., Ph.D. |
| collection | DOAJ |
| description | After a myocardial infarction (MI), an increase in the cardiac ratio of matrix metalloproteinases (MMPs) relative to their inhibitors (TIMPs) causes extracellular matrix modulation that leads to ventricular dilatation and congestive heart failure. Cell therapy can mitigate these effects. In this study, we tested whether increasing MMP inhibition via cell-based gene transfer of Timp-3 further preserved ventricular morphometry and cardiac function in a rat model of MI. We also measured the effect of treatment timing. We generated MI (coronary artery ligation) in adult rats. Three or 14 days later, we implanted medium (control) or vascular smooth muscle cells transfected with empty vector (VSMCs) or Timp-3 (C-TIMP-3) into the peri-infarct region ( n = 15—24/group). We assessed MMP-2 and −9 expression and activity, TIMP-3, and TNF-α expression, cell apoptosis, infarct size and thickness, ventricular morphometry, and cardiac function (by echocardiography). Relative to medium, VSMCs delivered at either time point significantly reduced cardiac expression and activity of MMP-2 and −9, reduced expression of TNF-α, and increased expression of TIMP-3. Cell therapy also reduced apoptosis and scar area, increased infarct thickness, preserved ventricular structure, and reduced functional loss. All these effects were augmented by C-TIMP-3 treatment. Survival and cardiac function were significantly greater when VSMCs or C-TIMP-3 were delivered at 3 (vs. 14) days after MI. Upregulating post-MI cardiac TIMP-3 expression via cell-based gene therapy contributed additional regulation of MMP, TIMP, and TNF-α levels, thereby boosting the structural and functional effects of VSMCs transplanted at 3 or 14 days after an MI in rats. Early treatment may be superior to late, though both are effective. |
| first_indexed | 2024-12-13T09:52:58Z |
| format | Article |
| id | doaj.art-3aa524e8a99c432db16b6538eba473bc |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-12-13T09:52:58Z |
| publishDate | 2012-05-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-3aa524e8a99c432db16b6538eba473bc2022-12-21T23:51:53ZengSAGE PublishingCell Transplantation0963-68971555-38922012-05-012110.3727/096368911X601000Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic CardiomyopathyHai Tian M.D., Ph.D.0Ming-Li Huang1Kai-Yu Liu2Zhi-Bo Jia3Lu Sun4Shu-Lin Jiang5Wei Liu6Heather Y. Mcdonald Kinkaid7Jun Wu8Ren-Ke Li M.D., Ph.D.9Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaDepartment of Gynecology and Obstetrics, First Clinical College of Harbin Medical University, Harbin, ChinaKey Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaKey Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaKey Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaKey Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaKey Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, ChinaDepartment of Surgery, Division of Cardiovascular Surgery, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, CanadaDepartment of Surgery, Division of Cardiovascular Surgery, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, CanadaDepartment of Surgery, Division of Cardiovascular Surgery, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, CanadaAfter a myocardial infarction (MI), an increase in the cardiac ratio of matrix metalloproteinases (MMPs) relative to their inhibitors (TIMPs) causes extracellular matrix modulation that leads to ventricular dilatation and congestive heart failure. Cell therapy can mitigate these effects. In this study, we tested whether increasing MMP inhibition via cell-based gene transfer of Timp-3 further preserved ventricular morphometry and cardiac function in a rat model of MI. We also measured the effect of treatment timing. We generated MI (coronary artery ligation) in adult rats. Three or 14 days later, we implanted medium (control) or vascular smooth muscle cells transfected with empty vector (VSMCs) or Timp-3 (C-TIMP-3) into the peri-infarct region ( n = 15—24/group). We assessed MMP-2 and −9 expression and activity, TIMP-3, and TNF-α expression, cell apoptosis, infarct size and thickness, ventricular morphometry, and cardiac function (by echocardiography). Relative to medium, VSMCs delivered at either time point significantly reduced cardiac expression and activity of MMP-2 and −9, reduced expression of TNF-α, and increased expression of TIMP-3. Cell therapy also reduced apoptosis and scar area, increased infarct thickness, preserved ventricular structure, and reduced functional loss. All these effects were augmented by C-TIMP-3 treatment. Survival and cardiac function were significantly greater when VSMCs or C-TIMP-3 were delivered at 3 (vs. 14) days after MI. Upregulating post-MI cardiac TIMP-3 expression via cell-based gene therapy contributed additional regulation of MMP, TIMP, and TNF-α levels, thereby boosting the structural and functional effects of VSMCs transplanted at 3 or 14 days after an MI in rats. Early treatment may be superior to late, though both are effective.https://doi.org/10.3727/096368911X601000 |
| spellingShingle | Hai Tian M.D., Ph.D. Ming-Li Huang Kai-Yu Liu Zhi-Bo Jia Lu Sun Shu-Lin Jiang Wei Liu Heather Y. Mcdonald Kinkaid Jun Wu Ren-Ke Li M.D., Ph.D. Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy Cell Transplantation |
| title | Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy |
| title_full | Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy |
| title_fullStr | Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy |
| title_full_unstemmed | Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy |
| title_short | Inhibiting Matrix Metalloproteinase by Cell-Based Gene Transfer Effectively Treats Acute and Chronic Ischemic Cardiomyopathy |
| title_sort | inhibiting matrix metalloproteinase by cell based gene transfer effectively treats acute and chronic ischemic cardiomyopathy |
| url | https://doi.org/10.3727/096368911X601000 |
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