Abstract | AIMS: METHODS AND RESULTS: We found that HSP70 serum levels, as well as the amount of HSP70 translocation to the cardiomyocyte membranes and the interstitial space, were elevated in the hypertensive mice caused by abdominal aortic constriction (AAC). Transcriptional inhibition of HSP70 expression by a specific heat shock transcript factor inhibitor, KNK437, reduced the serum level, and the re-distribution of HSP70. It promoted myocardial hypertrophy and cardiac dysfunctions although it protected animals from AAC-induced cardiac fibrosis. On the other hand, the functional antagonism of HSP70 by an anti-HSP70 antibody attenuated AAC-induced cardiac hypertrophy and fibrosis without adverse haemodynamic effects. The cardioprotective effect of the anti-HSP70 antibody was largely attributed to its ability to block AAC-activated immune response in the heart, as was indicated by suppressing the hypertension-enhanced conjugation of HSP70 with toll-like receptor 4, reducing heart-infiltrating macrophages, decreasing the expression of pro-inflammatory factor monocyte chemoattractant protein-1 and profibrotic factor transforming growth factor beta 1, and attenuating pro- hypertrophy signal MAPK P38 and ERK. CONCLUSION: These results indicate that intracellular and extracellular HSP70 have different roles in the regulation of cardiac remodelling and function in response to hypertension. Extracellular HSP70 is a potential therapeutic target against cardiac hypertrophy and fibrosis.
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Authors | Wen-Feng Cai, Xiao-Wei Zhang, Hui-Min Yan, Yong-Gang Ma, Xiao-Xing Wang, Jun Yan, Bing-Mu Xin, Xiao-Xi Lv, Qing-Qing Wang, Zi-Yan Wang, Hong-Zhen Yang, Zhuo-Wei Hu |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 88
Issue 1
Pg. 140-9
(Oct 01 2010)
ISSN: 1755-3245 [Electronic] England |
PMID | 20542874
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies
- Benzhydryl Compounds
- Ccl2 protein, mouse
- Chemokine CCL2
- HSP70 Heat-Shock Proteins
- KNK 437
- Pyrrolidinones
- Tgfb1 protein, mouse
- Tlr4 protein, mouse
- Toll-Like Receptor 4
- Transforming Growth Factor beta1
- Angiotensin II
- Extracellular Signal-Regulated MAP Kinases
- p38 Mitogen-Activated Protein Kinases
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Topics |
- Angiotensin II
(metabolism)
- Animals
- Antibodies
(administration & dosage)
- Benzhydryl Compounds
(administration & dosage)
- Blood Pressure
- Cardiomegaly
(immunology, metabolism, physiopathology)
- Chemokine CCL2
(metabolism)
- Disease Models, Animal
- Enzyme Activation
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Fibrosis
- HSP70 Heat-Shock Proteins
(antagonists & inhibitors, blood, genetics, immunology, metabolism)
- Hypertension
(immunology, metabolism, physiopathology)
- Male
- Mice
- Mice, Inbred ICR
- Myocardium
(immunology, metabolism, pathology)
- Protein Transport
- Pyrrolidinones
(administration & dosage)
- Signal Transduction
- Time Factors
- Toll-Like Receptor 4
(metabolism)
- Transcription, Genetic
- Transforming Growth Factor beta1
(metabolism)
- Ventricular Remodeling
(drug effects)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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