Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction

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.

Mast Cell Degranulation Increases Mouse Mast Cell Protease 4–Dependent Vasopressor Responses to Big Endothelin-1 But Not Angiotensin I

“…More recently, Pinke et al (2020) showed that mast cell stabilization with ketotifen lowered disease prevalence and severity and the expression of chymase and carboxypeptidase A in mice, thus supporting a potentially therapeutic indication for mast cell stabilizers in multiple sclerosis (Pinke et al, 2020). Deleterious roles for mast cell-derived chymase have also been shown in experimental models of cardiac infarct, ischemia/reperfusion, and atherosclerosis (Jin, 2003;Tejada et al, 2016;Houde et al, 2018). Finally, patients with myocardial infarction show increased levels of plasmatic and cardiac and chymase activity in the same organ (Oka et al, 2014).…”

Detection of cardiac apoptosis by [18F]ML-10 in a mouse model of permanent LAD ligation

“…We, however, could not detect a signal of active caspase-3 in these early time frames. Published literature suggests that this staining is rather feasible at 72 h of permanent LAD ligation [ 35 ].…”

The Roles of Noncardiomyocytes in Cardiac Remodeling

“…mMCP4 was extensively expressed in MCs post MI, and the deficiency of mMCP4 played a protective role in murine cardiac function after coronary artery ligation, which was characterized by reduced CM apoptosis, reduced accumulation of immune cells, impaired TGF-β signaling, enhanced ECM degradation, and amelioration of the ejection fraction [126]. Similarly, another finding demonstrated that in mMCP-4 knockout mice, the size of the infarcted area, ventricular remodeling, and apoptotic signaling were prominently reduced compared to those in the WT congeners [127]. Insulin-like growth factor-1 (IGF-1), a protective polypeptide, was degraded by mMCP4.…”