Cross your heart? Collagen cross-links in cardiac health and disease

Abstract

Extracellular matrix (ECM) remodeling occurs in response to various cardiac insults including infarction, pressure overload and dilated myopathies. Each type of remodeling necessitates distinct types of ECM turnover and deposition yet an increase in myocardial fibrillar collagen content is appreciated as a contributing feature to cardiac dysfunction in each of these pathologies. In addition, aging, is also associated with increases in cardiac collagen content. The importance of characterizing differences in ECM composition and processes used by cardiac fibroblasts in the assembly of fibrotic collagen accumulation is critical for the design of strategies to reduce and ultimately regress cardiac fibrosis. Collagen cross-linking is one factor that influences collagen deposition and insolubility with direct implications for tissue properties such as stiffness. In this review, three different types of collagen cross-links shown to be important in cardiac fibrosis will be discussed; those catalyzed by lysyl oxidases, those catalyzed by transglutaminases, and those that result from non-enzymatic modification by the addition of advanced glycation end products. Insight into cellular mechanisms that govern collagen cross-linking in the myocardium will provide novel pathways for exploring new treatments to treat diseases associated with cardiac fibrosis.

Keywords: Fibromodulin; Lysyl oxidase; Periostin; SPARC; Thrombospondin; Transglutaminase.

Fig. 1.

Schematic representing the three types of collagen cross-links discussed in the text. A) In healthy myocardium, lysyl oxidase family members represented by LOX catalyze inter- and intramolecular cross-link formation via modified amino acids in the telopeptide regions of fibrillar collagens specifically involving lysine (purple bars) and hydroxylysine (light blue bars) residues. Lysyl oxidase is secreted as prolysyl oxidase and activated by the action of bone morphogenic protein (BMP-1, blue arrow). The matricellular proteins periostin and thrombospondin (TSP, green oval) facilitate activation of lysyl oxidase by BMP-1. Evidence that periostin and TSP might also influence cross-linking via direct binding to fibrillar collagen and/or serve in scaffolding complexes that enhance procollagen processing is also supported (not shown). Fibromodulin (pink oval) influences cross-linking via direct binding to telopeptide regions of fibrillar collagens. Fibromodulin also binds to LOX and thus might direct enzymatic activity to specific sites of modification. Transglutaminases catalyze cross-linking (black bars) of collagen and fibronectin (yellow lines), an activity proposed to be regulated by the matricellular protein SPARC (yellow oval). Fibronectin assembly occurs via integrin interaction on fibroblasts. Advanced glycation end products (AGE)-modified cross-links (green bars) are also proposed to occur on lysine residues in telopeptide regions although other sites of AGE cross-links might also occur. B) In fibrotic myocardium, increases in amounts of fibrillar collagen are accompanied by increases in collagen cross-linking. Lysyl hydroxylase 2 activity is predicted to increase hydroxylysines residues in the telopeptide resulting in increased lysyl oxidase family catalyzed cross-links involving hydroxylysines (blue bars). Evidence that hydroxylysine residues are more resistant to fibrotic regression might contribute to accumulation of collagen fibrils in fibrosis. Activation of cardiac fibroblasts (purple structures represent stress fiber formation) enhances cell-mediated assembly of fibronectin networks predicted to facilitate collagen ECM assembly. Increases in LOX family members and transglutaminases from both resident and recruited inflammatory cells increase overall collagen cross-linking in the myocardium. AGE-dependent cross-links are particularly implicated in diabetic myopathies where increased amounts of circulating glucose lead to increases in glycation of ECM proteins including fibrillar collagens.