Abstract
This study tested the hypothesis that MMP-9−/−tPA−/− double knock out (i.e., MTDKO) plays a crucial role in the prognostic outcome after acute myocardial infarction (AMI by ligation of left-coronary-artery) in MTDKO mouse. Animals were categorized into sham-operated controls in MTDKO animals (group 1) and in wild type (B6: group 2), AMI-MTDKO (group 3) and AMI-B6 (group 4) animals. They were euthanized, and the ischemic myocardium was harvested, by day 60 post AMI. The mortality rate was significantly higher in group 3 than in other groups and significantly higher in group 4 than in groups 1/2, but it showed no difference in the latter two groups (all p < 0.01). By day 28, the left-ventricular (LV) ejection fraction displayed an opposite pattern, whereas by day 60, the gross anatomic infarct size displayed an identical pattern of mortality among the four groups (all p < 0.001). The ratio of heart weight to tibial length and the lung injury score exhibited an identical pattern of mortality (p < 0.01). The protein expressions of apoptosis (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP), fibrosis (Smad3/T-GF-ß), oxidative stress (NOX-1/NOX-2/oxidized-protein), inflammation (MMPs2,9/TNF-α/p-NF-κB), heart failure/pressure overload (BNP/ß-MHC) and mitochondrial/DNA damage (cytosolic-cytochrome-C/γ-H2AX) biomarkers displayed identical patterns, whereas the angiogenesis markers (small vessel number/CD31+cells in LV myocardium) displayed opposite patterns of mortality among the groups (all p < 0.0001). The microscopic findings of fibrotic/collagen deposition/infarct areas and inflammatory cell infiltration of LV myocardium were similar to the mortality among the four groups (all p < 0.0001). MTDKO strongly predicted unfavorable prognostic outcome after AMI.
Highlights
Abundant data have revealed that the myocardium of a failing heart (HF), i.e., resulting from myocardial infarction (MI), dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM), always undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix (ECM) proteins [1,2,3,4]
By day 3 after Acute Myocardial Infarction (AMI), the mortality rate was significantly higher in group 3 (AMI-MTDKO) than in groups 1 (sham-operated control (SC), i.e., Sham-operated mice (SC)-MTDKO), 2 (SC-B6) and 4 (AMI-B6) and significantly higher in group 4 than in groups 1 and 2 (40% vs. 15% vs. 0%, p < 0.01), but it showed no difference between groups 1 and 2 (Figure 1A)
By days 14 and 28 after the AMI procedure (Figure 1C,D), the Left ventricular ejection fraction (LVEF) was significantly lower in group 3 than in other groups and significantly lower in group 4 than in groups 1 and 2, but it did not differ between groups 1 and 2
Summary
Abundant data have revealed that the myocardium of a failing heart (HF), i.e., resulting from myocardial infarction (MI), dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM), always undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix (ECM) proteins [1,2,3,4]. Studies have shown that interstitial fibrosis and excessive accumulation of ECM proteins play crucial roles in regulating LV remodeling [5,6,7,8,9,10,11]. Fibrosis and excessive accumulation of ECM in HCM and MI have been shown to be highly associated with LV dysfunction HF [14,15], i.e., heart failure with reduced ejection fraction (HFrEF), and have been considered as key substrates for ventricular arrhythmias and sudden death [5]. Further analysis demonstrated that the underlying mechanism for protecting the brain infarct volume from acute IS is mainly through the accumulated ECM, i.e., tissue remodeling due to deficiency of MMP9, which acts as a proteolytic enzyme, protecting the brain from extensive hemorrhage and transforming the hemorrhagic effect [16]. We created a double knockout (DKO) mouse of MMP9−/−tPA−/− to validate our hypothesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
