Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

Abstract

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

Myofiber injury induces capillary disruption and regeneration of disorganized microvascular networks

“…This outcome suggests that while neutrophil activity contributes to capillary damage, additional mechanisms lead to EC death when skeletal muscle is injured. Candidates include toxic substances released from degenerating myofibers, reactive oxygen species, calpaindependent protein degradation, recruitment of proinflammatory cells including monocytes and macrophages (20,(31)(32)(33)(34).…”

Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction

“…In addition, cardiac fibroblasts produce hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and endothelial cells of coronary blood vessels upregulate the expression of vascular cell adhesion molecule 1 (VCAM-1) and selectins [ 11 ]. Moreover, the death of cardiomyocytes leads to the release of damage-associated molecular patterns (DAMPs), such as heat shock proteins, nuclear chromatin-binding protein high mobility group box 1, low molecular hyaluronic acid, fibronectin fragments, cardiac myosin, mitochondrial DNA and circulating extracellular RNA molecules [ 13 ]. DAMPs are recognized by pattern recognition receptors expressed on neutrophils, macrophages, dendritic cells and other cells of the immune system [ 13 ].…”

“…Moreover, the death of cardiomyocytes leads to the release of damage-associated molecular patterns (DAMPs), such as heat shock proteins, nuclear chromatin-binding protein high mobility group box 1, low molecular hyaluronic acid, fibronectin fragments, cardiac myosin, mitochondrial DNA and circulating extracellular RNA molecules [ 13 ]. DAMPs are recognized by pattern recognition receptors expressed on neutrophils, macrophages, dendritic cells and other cells of the immune system [ 13 ]. All of the aforementioned events result in the massive influx of circulating monocytes and neutrophils into the infarcted tissue [ 11 ].…”

Plasma Heat Shock Protein 70 Is Associated With the Onset of Acute Myocardial Infarction and Total Occlusion in Target Vessels

“…Heat shock proteins (HSPs) are known as molecular chaperones that function in protein folding ( 1 ), usually induced by hyperthermia, which may also indicate other forms of cellular stress such as lipopolysaccharide, high blood pressure, infection ( 2 ), and ischemic injury ( 1 ). Despite the view that HSPs may act as damage-associated molecular patterns (DAMPs) during the ischemic damage to interact with pattern recognition receptors (PRRs) and induce a strong immune response in acute myocardial infarction (AMI), HSPs are not bona fide intracellular molecules that normally are not exposed to an extracellular environment ( 3 ), and they are detectable in normal circulation. Heat shock protein 70 (HSP70) is one of the members of HSPs, which both regulates intracellular homeostasis and can be released to the extracellular milieu in response to AMI ( 4 , 5 ).…”

“…The role of HSP70 in AMI is therefore complex and ambiguous ( 3 ); whether circulating HSP70 could be utilized as a biomarker and whether the marker is friend or foe after AMI remains debated. The association of HSP70 with features of lesions in coronary artery disease (CAD) remains uncertain.…”