Amplified Bioactive Signaling and Proteolytic Enzymes Following Ischemia Reperfusion and Aging

Abstract

Left ventricular (LV) remodeling, defined as changes in myocardial structure and geometry, is considered to be a fundamental milestone in the progression to heart failure. This is particularly true in the clinical context of a myocardial infarction (MI) whereby adverse LV remodeling is directly associated with the progression to heart failure and increased morbidity and mortality.1 LV remodeling is a multifactorial process which includes changes within the myocardial, vascular and extracellular matrix (ECM). However, in terms of post-MI remodeling, changes in myocardial growth/viability and ECM structure/composition are ubiquitous events, and occur in a heterogeneous fashion within the remote viable myocardium, the myocardial region surrounding the MI (borderzone), and the MI scar itself. It is the summation of the alterations within both the cellular and extracellular compartments, which occur in all these regions post-MI, which promulgate adverse LV remodeling and ultimately the progression to heart failure. Through the use of animal models and clinical translational studies, certain signaling and proteolytic events have been identified to uniformly occur following an MI, and likely induce the cascade of events which yield changes in myocardial structure and function.2–8 In this issue of Circulation, Jugdutt and colleagues report how activation of a specific signaling pathway, the angiotensin-II receptor, influences a number of critical cellular signaling and ECM proteolytic events which can contribute to adverse LV remodeling.2 These investigators examined a number of critical pathways following a period of ischemia and reperfusion, which resulted in a significant and relevant MI. These investigators not only examined these signaling/proteolytic events in a clinically relevant model of MI, but more importantly examined the post-MI remodeling process within the aging myocardium. The findings from this study are important for 2 reasons. First, this study clearly demonstrated that important interactions occurred between the angiotensin-II receptor and the induction of bioactive molecules and proteases following an acute MI. Second, this study demonstrated that an amplified response occurs between these intersecting pathways within the aging myocardium following an acute MI. Taken together, the findings by Jugdutt and colleagues provide mechanistic evidence that the elderly myocardium is a more vulnerable substrate to an ischemic insult, and that this is likely due to enhanced/amplified induction of signaling cascades and proteolytic events that would directly contribute to a more advanced and accelerated LV remodeling process.