Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy
Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5- to 6-month-old beta-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (approximately 2.5 fold) but were reduced in the atorvastatin group. Levels of GTP- and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2005 |
|---|---|
| Erschienen: |
2005 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:97 |
|---|---|
| Enthalten in: |
Circulation research - 97(2005), 3 vom: 05. Aug., Seite 285-92 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Senthil, Vinitha [VerfasserIn] |
|---|
| Anmerkungen: |
Date Completed 20.10.2005 Date Revised 08.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM156573555 |
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| 100 | 1 | |a Senthil, Vinitha |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy |
| 264 | 1 | |c 2005 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Revised 08.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5- to 6-month-old beta-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (approximately 2.5 fold) but were reduced in the atorvastatin group. Levels of GTP- and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a DNA, Mitochondrial |2 NLM | |
| 650 | 7 | |a Heptanoic Acids |2 NLM | |
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| 700 | 1 | |a Chen, Suet N |e verfasserin |4 aut | |
| 700 | 1 | |a Tsybouleva, Natalie |e verfasserin |4 aut | |
| 700 | 1 | |a Halder, Tripti |e verfasserin |4 aut | |
| 700 | 1 | |a Nagueh, Sherif F |e verfasserin |4 aut | |
| 700 | 1 | |a Willerson, James T |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Marian, A J |e verfasserin |4 aut | |
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