Abstract
Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI). The mechanisms of captopril action remain inadequately understood due to its diverse effects on multiple signalling pathways at different time periods following MI. Here we aimed to establish the role of captopril in late-stage post-MI remodelling. Left anterior descending artery (LAD) ligation or sham surgery was carried out in male C57BL/6J mice. Seven days post-surgery LAD ligated mice were allocated to daily vehicle or captopril treatment continued over four weeks. To provide comprehensive characterization of the changes in mouse heart following MI a 3D light sheet imaging method was established together with automated image analysis workflow. The combination of echocardiography and light sheet imaging enabled to assess cardiac function and the underlying morphological changes. We show that delayed captopril treatment does not affect infarct size but prevents left ventricle dilation and hypertrophy, resulting in improved ejection fraction. Quantification of lectin perfused blood vessels showed improved vascular density in the infarct border zone in captopril treated mice in comparison to vehicle dosed control mice. These results validate the applicability of combined echocardiographic and light sheet assessment of drug mode of action in preclinical cardiovascular research.
Highlights
Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI)
Optical clearing of mouse and even human organs and tissues combined with light sheet fluorescence microscopy (LSFM) has opened new possibilities for visualizing cells and activated signalling pathways in 3 D20–24, but shortage of automated quantitative analysis platforms is still a bottleneck and no studies have so far demonstrated the sensitivity of the method in preclinical pharmacological cardiovascular research
Systolic dysfunction and cardiac dilation were evident by decreased ejection fraction (EF) (p < 0.001, Left anterior descending artery (LAD)—vehicle and LAD—Captopril vs. Sham—vehicle) and increased LV internal diameter in diastole (LVIDd) (p < 0.001, LAD—Captopril vs. Sham—vehicle; p < 0.01, LAD—vehicle vs. Sham—vehicle) in LAD ligated animals compared to sham operated mice (Fig. 1b,e)
Summary
Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI). Quantification of lectin perfused blood vessels showed improved vascular density in the infarct border zone in captopril treated mice in comparison to vehicle dosed control mice These results validate the applicability of combined echocardiographic and light sheet assessment of drug mode of action in preclinical cardiovascular research. Left anterior descending artery (LAD) ligation in mice and rats remains the most common technique in preclinical pharmacological research to assess the efficacy of treatment options for M I9. Optical clearing of mouse and even human organs and tissues combined with light sheet fluorescence microscopy (LSFM) has opened new possibilities for visualizing cells and activated signalling pathways in 3 D20–24, but shortage of automated quantitative analysis platforms is still a bottleneck and no studies have so far demonstrated the sensitivity of the method in preclinical pharmacological cardiovascular research. The current study was aimed at developing a light sheet imaging platform for myocardial infarction analysis and to use it for demonstrating the mode of action of delayed captopril treatment
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