Abstract
Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague–Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca2+-sensitivities of force production (pCa50) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa50, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.
Highlights
Rapid reperfusion has dramatically reduced short-term mortality of patients with acute myocardial infarction (MI), current management strategies cannot prevent the development of post-ischemic chronic heart failure in a significant proportion of MI cases [1]
Our results present new evidence for post-ischemic myocardial remodeling and its prevention by repeated remote ischemic conditioning (rRIC) in rat hearts
We show that left ventricular (LV) performance is tightly coupled to a set of interacting variables: tissue activities of Angiotensin-converting enzyme (ACE) and Angiotensin-converting enzyme 2 (ACE2), the Ca2+ -sensitivity of force production, and myofilament protein phosphorylation six weeks after MI
Summary
Rapid reperfusion has dramatically reduced short-term mortality of patients with acute myocardial infarction (MI), current management strategies cannot prevent the development of post-ischemic chronic heart failure in a significant proportion of MI cases [1]. Of the β-adrenergic cascade) implicate roles for over-activated neuro-humoral signaling in myocardial remodeling [1] During this maladaptive process, the myocardium develops morphological and functional alterations [2], whereby changes in the expression and phosphorylation of cardiomyocyte proteins render the heart limited in its mechanical performance. We focused on LV alterations in a rat model of post-ischemic remodeling and its prevention by rRIC To these ends, tissue activities of the angiotensin-converting enzyme (ACE), and angiotensin-converting enzyme 2 (ACE2) were assayed. Our data illustrate rRIC with a potential to normalize myocardial ACE and ACE2 activities, cardiomyocyte signaling and function, and thereby to improve post-ischemic systolic performance
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