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An Intact Pericardium Ischemic Rodent Model
Published on: September 2, 2021
Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture
Mikhail A Kolpakov1, Xinji Guo1, Khadija Rafiq2
1Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (M.A.K., X.G., L.V., B.H., R.S., T.W., X.F., D.G.T., J.C.K., S.P.K., S.R.H., A.S.).
Insights
Protease-activated receptor 4 (Par4) plays a dual role in heart attack recovery. While inhibiting Par4 may help in the acute phase, it worsens long-term healing and increases cardiac rupture risk.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Cardiac rupture is a significant cause of death following myocardial infarction (MI).
- Despite advances in reperfusion therapy, mortality rates from cardiac rupture remain high.
- The role of thrombolytic therapy in accelerating cardiac rupture is debated.
Purpose of the Study:
- To investigate the expression and function of protease-activated receptor 4 (Par4) in the context of myocardial infarction (MI).
- To determine the impact of Par4 deletion on cardiac remodeling, function, and healing post-MI.
Main Methods:
- Analysis of Par4 mRNA and protein levels in mouse hearts after MI.
- Assessment of cardiac remodeling and function using echocardiography, immunohistochemistry, and flow cytometry in wild-type and Par4-deficient mice.
- In vitro and in vivo studies on neutrophil apoptosis and inflammatory responses.
Main Results:
- Par4 expression increased in mouse hearts post-MI and in response to hypertrophic/inflammatory stimuli.
- Par4-deficient mice exhibited reduced myocyte apoptosis, smaller infarct size, and better acute functional recovery.
- Conversely, Par4-deficient mice showed impaired long-term cardiac function, increased myocardial rupture, and higher mortality, linked to delayed neutrophil apoptosis and impaired inflammation resolution.
Conclusions:
- Par4 is crucial for neutrophil apoptosis and timely inflammation resolution, essential for effective myocardial healing post-MI.
- Par4 inhibition may be beneficial in acute ischemic phases but detrimental for long-term recovery.
- Targeting Par4 requires careful consideration of the timing and duration of treatment to avoid adverse effects on cardiac repair.
Background:
Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.
Methods:
We analyzed protease-activated receptor 4 (Par4) expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function after MI by echocardiography, quantitative immunohistochemistry, and flow cytometry.
Results:
Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size, and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4-/- mice showed impaired cardiac function, greater rates of myocardial rupture, and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4-/- mice demonstrated a greater infarct expansion, increased cardiac hemorrhage, and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared with WT. Par4 deficiency also attenuated neutrophil apoptosis in vitro and after MI in vivo and impaired inflammation resolution in infarcted myocardium. Transfer of Par4-/- neutrophils, but not of Par4-/- platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage, and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4-/- mice restored inflammation resolution, reduced cardiac rupture incidence, and improved cardiac function after MI.
Conclusions:
These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as a potential therapy that should be limited to the acute phases of ischemic insult and avoided for long-term treatment after MI.
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