Cardiac extracellular matrix remodeling: fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC)

Abstract

The cardiac interstitium is a unique and adaptable extracellular matrix (ECM) that provides a milieu in which myocytes, fibroblasts, and endothelial cells communicate and function. The composition of the ECM in the heart includes structural proteins such as fibrillar collagens and matricellular proteins that modulate cell:ECM interaction. Secreted Protein Acidic and Rich in Cysteine (SPARC), a collagen-binding matricellular protein, serves a key role in collagen assembly into the ECM. Recent results demonstrated increased cardiac rupture, dysfunction and mortality in SPARC-null mice in response to myocardial infarction that was associated with a decreased capacity to generate organized, mature collagen fibers. In response to pressure overload induced-hypertrophy, the decrease in insoluble collagen incorporation in the left ventricle of SPARC-null hearts was coincident with diminished ventricular stiffness in comparison to WT mice with pressure overload. This review will focus on the role of SPARC in the regulation of interstitial collagen during cardiac remodeling following myocardial infarction and pressure overload with a discussion of potential cellular mechanisms that control SPARC-dependent collagen assembly in the heart.

Figure 1

Regulatory mechanisms controlling collagen homeostasis. This review will focus on the proposed function of SPARC in post-synthetic procollagen processing to influence collagen deposition in the heart.

Figure 2. Model of Proposed Function of SPARC in Post-synthetic Procollagen Processing

Panel A: Procollagen processing into a mature collagen fibril in normal wild type (WT) mouse myocardium: 1. Procollagen secreted into the extracellular space. 2. SPARC binds to procollagen (or procollagen is secreted bound by SPARC). 3. SPARC decreases collagen association with cell surface receptors (or a subset of receptors). 4. C-terminal propeptide of procollagen cleaved by BMP-1 (enhanced by PCPE activity e.g. PCPE-1, PCPE-2, and Srfp2), 5. N-terminal propeptide cleaved by ADAMTS-2/14, 6. Collagen stabilized in mature fibrils by formation of cross-links. Panel B: SPARC deletion alters the balance between processing to mature collagen fibrils and degradation; increased cell-associated collagen is degraded and/or taken up by cell-surface collagen receptors resulting in less procollagen effectively processed into mature fibrils and decreased levels of interstitial collagen assembled into insoluble fibers. Panel C: SPARC over-expression further diminishes cell-associated collagen and promotes efficient procollagen processing and incorporation of collagen into fibrils thus enhancing deposition of collagen and formation of mature fibers. SPARC: Secreted Protein Acidic and Rich in Cysteine, BMP: Bone Morphogenetic Protein, PCPE: Procollagen C-Proteinase Enhancer 1, other enhancers of activity include PCPE-2 and Srfp2. ADAMTS: A Disintegrin-like and Metalloproteinase Domain with Thrombospondin Type Motif, MT1-MMP: Membrane-Type Matrix Metalloproteinase.