Selectins and Immune Cells in Acute Myocardial Infarction and Post-infarction Ventricular Remodeling: Pathophysiology and Novel Treatments

Abstract

The glycosciences aim to understand the impact of extracellular and intracellular carbohydrate structures on biological function. These glycans primarily fall into three major groups: lipid-linked carbohydrates that are referred to as glycosphingolipids or simply glycolipids; relatively short carbohydrate chains that are often O- or N-linked to proteins yielding common glycoproteins; and extended linear polymeric carbohydrate structures that are referred to as glycosaminoglycans (GAGs). Whereas, the impact of such carbohydrate structures has been extensively examined in cancer biology, their role in acute and chronic heart disease is less studied. In this context, a growing body of evidence indicates that glycans play an important role in immune mediated cell recruitment to damaged heart tissue to initiate wound healing and repair after injury. This is particularly important following ischemia and reperfusion that occurs in the heart in the setting of acute myocardial infarction. Here, immune system-mediated repair of the damaged myocardium plays a critical role in determining post-infarction ventricular remodeling, cardiac function, and patient outcome. Further, alterations in immune cell activity can promote the development of heart failure. The present review summarizes our current understanding of the phases of immune-mediated repair following myocardial infarction. It discusses what is known regarding glycans in mediating the recruitment of circulating immune cells during the early inflammatory stage of post-infarction repair, with focus on the selectin family of adhesion molecules. It offers future directions for research aimed at utilizing our knowledge of mechanisms underlying immune cell recruitment to either modulate leukocyte recruitment to the injured tissue or enhance the targeted delivery of biologic therapeutics such as stem cells in an attempt to promote repair of the damaged heart.

Keywords: glycan; heart disease; leukocyte-endothelial cell adhesion; mesenchymal (stromal) stem cells; myocardial infarction; post-infarct repair; sL; sP-selectin); selectin (sE; stem cells.

Figure 1

Cardiac repair after myocardial infarction. (A) The three phases of repair. (B) Temporal changes in leukocyte populations during repair phase.

Figure 2

Selectin ligand biosynthesis. (A) Sialofucosylated selectin ligands found on leukocytes are composed of at least one α(2,3) sialic acid and one α(1,3) fucose, typically on a Type-II lactosamine chain that may repeat. (B) Human leukocyte rolling on HUVEC monolayer is resistant to pronase digestion, but this is not the case for mice. * and †: P < 0.05 for rolling and adherent cells, respectively. (C) Selectin ligand biosynthesis at the N-terminus of PSGL-1. Competing pathways regulate the biosynthesis of the sialyl Lewis-X (sLe^x) epitope on core-2 based O-glycans. These competing enzymes are the core2 GlcNAc-transferase, ST3GaI-I, and ST6GaINAc enzymes. (B) is adapted from Mondal et al. (58) with permission.

Figure 3

Leukocyte-endothelial cell adhesion cascade. (A) Schematic depicts results from studies using human cells. The sialyltransferase ST3GaI4 is indispensable for all aspects of leukocyte adhesion. O-glycans are important for leukocyte capture from flow along with N-glycans. N-glycans largely control leukocyte rolling velocity with glycolipids also contributing to the transition to firm arrest. Besides cell adhesion, emerging evidence points to a role for glycans in also regulating cell activation and the transition to firm arrest. (B) Endowing heterologous cell types (like Mesenchymal Stem Cells, MSCs) with selectin scaffold proteins (“right scaffold”) along with enzymes facilitating the construction of sialofucosylated glycans (“right sugars”) can enable stem cell capture and rolling on the inflamed endothelium.