Extracellular matrix turnover and signaling during cardiac remodeling following MI: causes and consequences

Abstract

The concept that extracellular matrix (ECM) turnover occurs during cardiac remodeling is a well-accepted paradigm. To date, a multitude of studies document that remodeling is accompanied by increases in the synthesis and deposition of ECM components as well as increases in extracellular proteases, especially matrix metalloproteinases (MMPs), which break down ECM components. Further, soluble ECM fragments generated from enzymatic action serve to stimulate cell behavior and have been proposed as candidate plasma biomarkers of cardiac remodeling. This review briefly summarizes our current knowledge base on cardiac ECM turnover following myocardial infarction (MI), but more importantly extends discussion by defining avenues that remain to be explored to drive the ECM remodeling field forward. Specifically, this review will discuss cause and effect roles for the ECM changes observed following MI and the potential role of the ECM changes that may serve as trigger points to regulate remodeling. While the pattern of remodeling following MI is qualitatively similar but quantitatively different from various types of injury, the basic theme in remodeling is repeated. Therefore, while we use the MI model as the prototype injury model, the themes discussed here are also relevant to cardiac remodeling due to other types of injury.

Figure 1

Post-MI, the net ECM response is determined by the balance between ECM construction and destruction. If ECM accumulation predominates, then fibrosis can predispose the LV to congestive heart failure and arrhythmias. If ECM degradation predominates, then wall thinning can lead to LV aneurysm and rupture. Both pathways interact and feed on each other.

Figure 2

Infarct size predicts the average, but not the individual, LV remodeling response. For 65 C57/BL6J mice examined at day 7 post-MI, infarct size positively associated with the change in end diastolic dimension. However, for mice within a similar infarct size range (40–50% infarct size is highlighted by the dashed box), the response was not predictable.