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[Ischemic heart disease and apoptosis]
G Takemura1, M Ohno, H Fujiwara
1Second Department of Internal Medicine, Gifu University School of Medicine.
Insights
Apoptosis is thought to cause cell death in ischemic heart disease. However, this study found no evidence of apoptosis in cardiomyocytes after myocardial infarction, suggesting oncotic necrosis is the primary cell death mechanism.
Area of Science:
- Cardiovascular Research
- Cell Biology
- Pathology
Context:
- Apoptosis is widely believed to contribute to cardiomyocyte death following myocardial infarction.
- Previous studies relied on DNA fragmentation (TUNEL) to infer apoptosis, overlooking morphological evidence.
- Ischemic heart diseases, including myocardial infarction, involve complex cell death pathways.
Purpose:
- To investigate the role of apoptosis in cardiomyocyte death after myocardial infarction.
- To differentiate between apoptosis and other cell death mechanisms using combined ultrastructural and biochemical analysis.
- To clarify the cell death pathways involved in ischemic heart disease.
Summary:
- This study utilized electron microscopy combined with TUNEL (EM-TUNEL) to simultaneously assess ultrastructural changes and DNA fragmentation in cardiomyocytes post-myocardial infarction in rabbits.
- Results showed oncotic necrosis, not apoptosis, as the predominant cell death mechanism in infarcted cardiomyocytes across various reperfusion times.
- No ultrastructural evidence of apoptosis was found, challenging the prevailing view of apoptosis's role in acute ischemic cardiomyocyte death.
Impact:
- Revises the understanding of cardiomyocyte death mechanisms in myocardial infarction.
- Highlights the limitations of relying solely on DNA fragmentation assays for apoptosis detection.
- Suggests that 'apoptotic' cardiomyocytes observed in previous studies may represent a different form of cell death, potentially oncotic necrosis.
Abstract:
In the last three years, apoptosis has been reported to be associated with cell death in ischemic heart diseases, for examples, acute ischemic cardiomyocyte death in acute myocardial infarction; death of the salvaged cardiomyocytes in old myocardial infarction; death of infiltrated leukocytes and granulation tissue cells after myocardial infarction. Apoptosis-related proteins such as Bcl-2, Bax and Fas are expressed in the salvaged cardiomyocytes edging the infarct area. In vitro experiment using cultured cardiomyocytes suggested hypoxia causes apoptosis in them. Thus, apoptosis may play important roles in ischemic heart diseases. For detecting apoptosis, however, all of the previous studies on acute ischemic cardiomyocyte death depended exclusively on DNA fragmentation (biochemical marker of apoptosis) by a DNA ladder on gel electrophoresis and in situ nick end labeling (TUNEL), but never documented the ultrastructural changes characteristic of apoptosis (morphological marker of apoptosis). Then, we examined the ultrastructure and DNA fragmentation of cardiomyocytes in rabbit myocardial infarction using electron microscopy combined with TUNEL (EM-TUNEL) which allows simultaneous observation of both markers in the same cell. Rabbits underwent 30-min ischemia followed by 0-, 30-min, 2-, 4- and 24-h reperfusion of a left coronary artery. In the infarcted tissue, EM-TUNEL revealed oncotic necrosis of cardiomyocytes with or without DNA fragmentation in the 2-h, 4-h, and 24-h reperfusion groups, but no apoptotic cardiomyocytes in ultrastructure in any groups. Thus, so-called apoptotic cardiomyocytes after ischemia/reperfusion may belong to a different category from apoptosis.