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Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice
G Caligiuri1, B Levy, J Pernow
1Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.
Insights
Stress can trigger myocardial infarction in hypercholesterolemic mice with coronary atherosclerosis. Blocking endothelin receptor A prevented these stress-induced heart attacks, revealing a key signaling pathway.
Area of Science:
- Cardiovascular Biology
- Pathophysiology
Background:
- Myocardial infarction (MI) is associated with atherosclerosis, but the progression from asymptomatic coronary artery disease to acute MI remains incompletely understood.
- Hypercholesterolemia is a major risk factor for atherosclerosis and subsequent cardiovascular events.
Purpose of the Study:
- To investigate the link between coronary atherosclerosis and acute myocardial infarction in a mouse model.
- To determine the role of stress and endothelin receptor signaling in the development of stress-induced myocardial infarction.
Main Methods:
- Utilized apolipoprotein E-/- and low-density lipoprotein receptor-/- double knockout mice, a model for hypercholesterolemia and atherosclerosis.
- Induced acute ischemia through mental stress or hypoxia.
- Assessed myocardial damage via electrocardiography, troponin T leakage, and dehydrogenase release.
- Examined cardiomyocyte apoptosis, inflammation, and fibrosis.
- Evaluated the effect of an endothelin type A receptor blocker.
Main Results:
- Hypercholesterolemic mice developed both coronary atherosclerosis and myocardial infarction.
- Stress or hypoxia induced acute ischemia, leading to electrocardiographic changes and myocardial damage indicative of MI.
- Cardiomyocyte apoptosis, inflammation, and fibrosis were observed post-ischemia.
- Administration of an endothelin type A receptor blocker prevented these pathological changes.
Conclusions:
- Stress can precipitate acute myocardial infarction in the context of hypercholesterolemia-induced coronary atherosclerosis.
- Endothelin receptor signaling plays a critical role in mediating stress-induced myocardial infarction.
- Targeting endothelin receptors may offer a therapeutic strategy for preventing stress-related cardiac events in susceptible individuals.
Abstract:
Myocardial infarction is linked to atherosclerosis, yet the sequence leading from silent coronary atherosclerosis to acute myocardial infarction has remained unclear. Here we show that hypercholesterolemic apolipoprotein E-/- low density lipoprotein receptor-/- mice develop not only coronary atherosclerosis but also myocardial infarction. Exposure of mice to mental stress or hypoxia led to acute ischemia, which, in a large proportion of the mice, was followed by electrocardiographic changes, leakage of troponin T, and loss of dehydrogenase from the myocardium, all indicative of acute myocardial infarction. Apoptotic death of cardiomyocytes was followed by inflammation and fibrosis in the heart. All these pathological changes could be prevented by a blocker of the endothelin type A receptor. Thus, stress elicits myocardial infarction through endothelin receptor signaling in coronary atherosclerosis caused by hypercholesterolemia.