Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

Abstract

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.

Keywords: angiogenesis; fibroblasts; fibrosis; infarction; inflammation; macrophages.

Figure 1:. Damage-Associated Molecular Patterns (DAMPs) Initiate the post-infarction inflammatory response.

In the infarcted heart, dying cells, damaged extracellular matrix and infiltrating immune cells release a broad range of DAMPs, including the nuclear protein high mobility group box-1 (HMGB1), heat shock proteins (HSP), cardiac myosin, extracellular RNA (eRNA), the S100 proteins S100A8/A9, fibronectin extra domain A (EDA-Fn), low molecular weight hyaluronan (LMWH), and interleukin (IL)-1α. DAMPs bind to pattern recognition receptors expressed on the cell surface of immune cells, vascular cells, fibroblasts and cardiomyocytes, transducing downstream pro-inflammatory cascades and stimulating leukocyte recruitment.

Figure 2:. Temporal course of immune cell accumulation in myocardial infarction (MI) is linked to phase-specific cell functions.

ROS, reactive oxygen species. NET, neutrophils extracellular traps. LCN2, lipocalin 2. IL, interleukin. VEGF, vascular endothelial growth factor. SPP1, secreted phosphoprotein 1. TGF, transforming growth factor.

Figure 3:. The temporal dynamics of angiogenesis in healing myocardial infarction.

During the inflammatory phase, pericytes in the infarct zone disassociate from endothelial cells (EC), increasing microvascular permeability. During the proliferative phase, efferocytosis and components of the provisional extracellular matrix (such as fibronectin) stimulate an angiogenic phenotype in macrophages, promoting expression of Vascular Endothelial Growth Factor (VEGF) and deposition of angiogenic matricellular proteins. Macrophages and fibroblasts contribute to an angiogenic environment, resulting in formation of abundant microvessels that lack a mural cell coat. As the scar matures, pericytes are recruited through pathways involving PDGF-BB-PDGFRβ and TGF-β–TGFBR2 interactions, thus forming coated mature microvessels that stabilize the scar. PDGF, Platelet=Derived Growth Factor; TGF, Transforming Growth Factor.

Figure 4:. Fibroblast activation in cardiac repair.

During the proliferative phase of infarct healing, pericytes, macrophages and lymphocytes secrete a broad range of growth factors (such as Platelet-Derived Growth Factors (PDGF), Fibroblast Growth Factors (FGF) and Transforming Growth Factor (TGF)-β) and fibrogenic cytokines (such as Interleukin (IL)-4, IL-6, IL-10, IL-13) that stimulate fibroblasts promoting myofibroblast conversion and activation of a matrix-synthetic, matrix-preserving phenotype. Neurohumoral mediators (such as angiotensin II) and matricellular proteins that enrich the extracellular matrix (ECM) network also contribute to fibroblast activation. Scar maturation is associated with loss of myofibroblast features and acquisition of a matrifibrocyte phenotype by infarct fibroblasts. Fibroblast apoptosis may also contribute to de-activation of the fibrogenic response.