MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin
Copyright © 2021 Elsevier Inc. All rights reserved..
PURPOSE: Cardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a maladaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra- and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction.
METHODS: Male Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed.
RESULTS: 6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline.
CONCLUSION: Hypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:193 |
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| Enthalten in: |
Biochemical pharmacology - 193(2021) vom: 13. Nov., Seite 114744 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Parente, Juliana Montenegro [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.01.2022 Date Revised 06.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2021.114744 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM329967215 |
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| 100 | 1 | |a Parente, Juliana Montenegro |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin |
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| 500 | |a Date Completed 06.01.2022 | ||
| 500 | |a Date Revised 06.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a PURPOSE: Cardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a maladaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra- and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction | ||
| 520 | |a METHODS: Male Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed | ||
| 520 | |a RESULTS: 6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline | ||
| 520 | |a CONCLUSION: Hypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cardiac hypertrophy | |
| 650 | 4 | |a Dystrophin | |
| 650 | 4 | |a Hypertension | |
| 650 | 4 | |a Matrix metalloproteinase | |
| 650 | 4 | |a Troponin I | |
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| 700 | 1 | |a Blascke de Mello, Marcela Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Pedro Henrique Leite da |e verfasserin |4 aut | |
| 700 | 1 | |a Omoto, Ana Carolina Mieko |e verfasserin |4 aut | |
| 700 | 1 | |a Pernomian, Laena |e verfasserin |4 aut | |
| 700 | 1 | |a Oliveira, Isadora Sousa de |e verfasserin |4 aut | |
| 700 | 1 | |a Mahmud, Zabed |e verfasserin |4 aut | |
| 700 | 1 | |a Fazan, Rubens |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Arantes, Eliane Candiani |e verfasserin |4 aut | |
| 700 | 1 | |a Schulz, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Michele Mazzaron de |e verfasserin |4 aut | |
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