Abstract
Chymase, a mast cell serine protease involved in the generation of multiple cardiovascular factors, such as angiotensin II and endothelin-1 (ET-1), is elevated and participates in tissue degeneration after permanent myocardial infarction (PMI). Anesthetized 4-month old male wild-type (WT) C57BL/6J mice and mouse mast cell protease-4 knockout (mMCP-4 KO) congeners were subjected to ligation of the left anterior descending (LAD) coronary artery. A group of mice was then subjected to Kaplan-Meier 28-day survival analysis. In another group of mice, 18F-fluorodeoxyglucose positron emission tomography (PET) was performed to evaluate heart function and the infarcted zone 3 days post-PMI surgery. Cardiac morphology following PMI was evaluated on formalin-fixed heart slices and glycoproteomic analysis was performed using mass spectrometry. Finally, cardiac and lung tissue content of immunoreactive ET-1 was determined. PMI caused 60% mortality in WT mice, due to left ventricular wall rupture, and 7% in mMCP-4 KO mice. Cardiac PET analysis revealed a significant reduction in left ventricular volume (systolic and diastolic) and preserved the ejection fraction in mMCP-4 KO compared to WT animals. The infarcted area, apoptotic signaling and wall remodeling were significantly decreased in mMCP-4 KO mice compared to their WT congeners, while collagen deposition was increased. Glycoproteomic analysis showed an increase in apolipoprotein A1, an established chymase substrate in mMCP-4 KO mice compared to WT mice post-PMI. ET-1 levels were increased in the lungs of WT, but not mMCP-4 KO mice, 24 h post-PMI. Thus, the genetic deletion of mMCP-4 improved survival and heart function post-PMI.
Highlights
Myocardial remodeling and fibrosis after heart failure are associated with increased mast cell density, and mast-cell deficient mice show an improved prognosis following myocardial infarction (Levick et al, 2011)
We demonstrate in the present study the profound impact of the genetic repression of mouse mast cell protease-4 (mMCP-4) in mice subjected to irreversible left anterior descending (LAD) coronary artery ligation
Necropsy revealed that cardiac rupture was the cause of death in all 9 WT mice that did not complete the survival study, but no occurrence was found in mouse mast cell protease (mMCP)-4 KO mice (Figure 1B and Table 1)
Summary
Myocardial remodeling and fibrosis after heart failure are associated with increased mast cell density, and mast-cell deficient mice show an improved prognosis following myocardial infarction (Levick et al, 2011). A heparinbound serine protease with chymotrypsin-like activity, is one of the major components of cardiac mast cell granules. Mouse chymases include mouse mast cell protease (mMCP)-1, -4, -5, and -9. The closest mouse analog to human chymase, in terms of localization, substrate specificity and storage properties is mMCP-4 (Pejler et al, 2010). Chymase activity in the mouse heart is primarily due to mMCP-4 expression (Houde et al, 2013). Cardiovascular targets of chymase in mice and humans include the activation of angiotensin-II (Ang-II), endothelin-1 (ET-1) and matrix metalloproteinase 9 (MMP-9) as well as the degradation of the matrix protein fibronectin (Balcells et al, 1997; Houde et al, 2013; Semaan et al, 2015; Caughey, 2016)
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