Using Extracellular Matrix Proteomics to Understand Left Ventricular Remodeling

Abstract

Survival following myocardial infarction (MI) has improved substantially over the last 40 years; however, the incidence of subsequent congestive heart failure has dramatically increased as a consequence. Discovering plasma markers that signify adverse cardiac remodeling may allow high-risk patients to be recognized earlier and may provide an improved way to assess treatment efficacy. Alterations in extracellular matrix (ECM) regulate cardiac remodeling following MI and potentially provide a large array of candidate indicators. The field of cardiac proteomics has progressed rapidly over the past 20 years, since publication of the first two-dimensional electrophoretic gels of left ventricle proteins. Proteomic approaches are now routinely utilized to better understand how the left ventricle responds to injury. In this review, we will discuss how methods have developed to allow comprehensive evaluation of the ECM proteome. We will explain how ECM proteomic data can be used to predict adverse remodeling for an individual patient and highlight future directions. Although this review will focus on the use of ECM proteomics to better understand post-MI remodeling responses, these approaches have applicability to a wide-range of cardiac pathologies, including pressure overload hypertrophy, viral myocarditis, and non-ischemic heart failure.

Transformative Impact of Proteomics on Cardiovascular Health and Disease

“…19 Although hundreds of serum and plasma proteomic studies have been published, no single optimal anticoagulant agent has been established for these types of samples, in part because downstream applications may necessitate the use of different anticoagulant agents (eg, when measuring matrix metalloproteinase activity that is inhibited by EDTA or when assessing PTMs). 20 Some sample preparation protocols induce artifactual modifications, including S-thiolation modifications and methylation. 21,22 A report of results collected from 35 different laboratories that analyzed reference samples of human serum, EDTA-anticoagulated plasma, heparin-anticoagulated plasma, and citrate-anticoagulated plasma as part of the Human Plasma Proteome Project showed that EDTAanticoagulated plasma samples yielded the most reproducible …”

“…20,41 Protein extraction from cell membranes or the extracellular matrix is difficult because of the hydrophobic nature and poor solubility of these proteins. Poor solubility also limits the utility of 2-dimensional gel electrophoresis for membrane protein analysis.…”

The circular relationship between matrix metalloproteinase‐9 and inflammation following myocardial infarction

“…1; refs. [16][17][18][19][20]. MMP-9-mediated proteolysis of cytokines and chemokines is one way by which MMP-9 influences leukocyte trafficking and creates positive or negative feedback loops (19,39).…”

Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction

“…MMPs are a class of proteins responsible for proteolysis of ECM proteins, and MMP-9, amongst its myriad targets, degrades both collagen and fibronectin [13, 14]. Fragments of these proteins trigger inflammation and increase deposition of new ECM proteins including collagen I and III [15–17].…”