Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats

Hypoxia-inducible factor (HIF)-1α and-2α have diverse actions on the myocardium, but the importance of direct effects on cardiac myocytes is unclear. To define their regional accumulation and association with cardiomyocyte cell cycle change after myocardial infarction (MI), a rat MI model was establ...

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Bibliographic Details
Published in:Heart and vessels 2008-05, Vol.23 (3), p.193-200
Main Authors: Bai, Chen-Guang, Liu, Xiao-Hong, Liu, Wei-Qiang, Ma, Da-Lie
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biomedical Engineering and Bioengineering
Bromodeoxyuridine - metabolism
Cardiac Surgery
Cardiology
Cell cycle
Cell Cycle - genetics
Cell Proliferation
Cells, Cultured
Cellular biology
Disease Models, Animal
DNA Replication
Genetic Vectors
Heart
Heart attacks
Histones - metabolism
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Ki-67 Antigen - metabolism
Male
Medicine
Medicine & Public Health
Myocardial Infarction - genetics
Myocardial Infarction - metabolism
Myocardial Infarction - pathology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Original Article
Phosphorylation
Rats
Rats, Inbred Lew
Regeneration
RNA, Messenger - metabolism
Rodents
Transfection
Up-Regulation
Vascular Surgery
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Summary:Hypoxia-inducible factor (HIF)-1α and-2α have diverse actions on the myocardium, but the importance of direct effects on cardiac myocytes is unclear. To define their regional accumulation and association with cardiomyocyte cell cycle change after myocardial infarction (MI), a rat MI model was established by occluding the coronary arteries. To further prove a causative relationship between HIF and cell cycle regulation, cultured cardiomyocytes were transfected with adenoviral vectors carrying HIF-1α and HIF-2α. Two weeks after MI, both HIF-1α and HIF-2α mRNA were moderately increased in the infarcted left ventricle and noninfarcted left ventricle; HIF-2α amplification was also detected in areas of the interventricular septum and the right ventricle. In concordance with the changes in mRNA levels, immunohistochemistry signals of HIF-1α and HIF-2α were characterized by different regional distributions. In the myocardium adjacent to the infarcted tissue, a significant correlation between HIF-1α or HIF-2α and Ki-67 labeling index was observed ( P < 0.001). Immunohistochemical double staining showed that HIF positive cardiomyocytes underwent DNA synthesis. Cardiomyocytes treated with HIF-1α or -2α expressed Ki-67, phosphohistone H3, and bromodeoxyuridine effectively in vitro. In conclusion, HIF-1α and HIF-2α had a distinct spatial expression pattern in a rat model of ischemic heart disease. Both HIF subunits might be potent stimuli for cardiomyocytes to re-enter the cell cycle and initiate DNA synthesis.
ISSN:0910-8327
1615-2573
DOI:10.1007/s00380-007-1029-2