Cardiac troponin I (cTnI) is a key component of the Ca2+-regulatory mechanism of cardiac contractility. It is released into the circulation upon ischaemia and has become established as one of the principal diagnostic biomarkers of myocardial damage. The release of cTnI results in the generation of autoantibodies, and these have been suggested to play a pathogenic role. However, in this Edition of Clinical Science, Han, Y. et al. suggests that cTnI can act independently of immunological involvement, with the protein being found to increase infarct size caused by ischaemia/reperfusion (I/R) prior to the development of cTnI antibody. In vitro work shows that cTnI can induce increases in vascular cell adhesion molecule 1 (VCAM-1) expression and cell adhesion, with toll-like receptor 4 (TLR4) and nuclear factor kappa beta (NF-κB) involved in the downstream signalling.

The contractility of cardiac muscle at the myofilament level is principally controlled by the interaction of Ca2+ ions with the trimeric troponin complex located on the thin actin filaments. The rise in intracellular Ca2+ concentration during systole results in the binding of Ca2+ to troponin with the subsequent conformational changes in troponin and tropomyosin allowing productive binding of myosin heads to actin and hence sarcomere shortening; the decline in Ca2+ concentration during diastole results in dissociation of Ca2+ from troponin and relaxation [1]. During ischaemia and damage to heart tissue during myocardial infarction, intracellular proteins are released from cardiomyocytes into the circulation and the presence of cardiac-specific proteins has been used as a marker of disease. Initially, cardiac enzymes such as the MB isoform of creatine kinase were used to evaluate myocardial damage but more recently two subunits of troponin, cardiac troponin T (cTnT) and cardiac troponin I (cTnI), have become established as the principal diagnostic biomarkers due to their high cardiac specificity and their near absence in normal serum [2].

Intriguingly, it has begun to emerge that, beyond being a passive indicator of cardiomyocyte rupture, extracellular cTnI itself may have deleterious effects and be involved in pathogenesis. Initial evidence of this came from a mouse model deficient in the programmed cell death-1 (PD-1) receptor; these mice developed dilated cardiomyopathy (DCM) [3], apparently caused by autoantibodies against cTnI [4]. In further experiments, administration of exogenous cTnI monoclonal antibodies to wild-type mice induced dilatation and cardiac dysfunction. It was shown that these cTnI antibodies stained the surface of cardiomyocytes and in isolated cell studies augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes [4]. Furthermore it was found that immunization of mice with cTnI to produce autoantibodies resulted in myocardial inflammation followed by fibrosis and heart failure [5]. A report on patients with acute myocardial infarction appeared to support the findings in mice; the present study showed that the prevalence of cTnI antibodies in patients with acute myocardial infarction had a negative impact on the improvement of the left ventricular ejection fraction (LVEF) over a study period of 6–9 months [6]. However studies on the longer term recovery of patients with heart failure found that elevated cTnI antibodies did not correlate with greater symptoms of ischaemia or DCM, indeed in one study the opposite was found, and thus the role of cTnI autoantibodies in disease appears unclear [710].

The new study by Han and colleagues was initiated by the hypothesis that elevated extracellular cTnI level on its own (rather than cTnI autoantibodies) was capable of affecting cardiac function [11]. This was tested by assessing the effect of cTnI on cardiac infarct size in the acute phase of a myocardial ischaemia/reperfusion (I/R) rat model, importantly during a time window before the development of cTnI antibody. cTnI was shown to increase the infarct size caused by I/R and this was accompanied by an increase in inflammatory markers in both the heart and the circulation. Experiments using human umbilical vein endothelial cells showed that cTnI induced increase in vascular cell adhesion molecule 1 (VCAM-1) expression and VCAM-1 mediated adhesion of human monocytes (THP-1) to HUVECs, and this was able to be neutralized by VCAM-1 antibody. Blockade of either toll-like receptor 4 (TLR4) or nuclear factor kappa beta (NF-κB) inhibited the effect of cTnI on VCAM-1 expression and adhesion of monocytes to endothelial cells, thus suggesting that TLR4 and NF-κB were involved in the downstream signalling. This was supported by the finding that inhibition of TLR4 in rats reduced the increase in I/R injury mediated by cTnI. It was concluded that cTnI exacerbates myocardial I/R injury by inducing the adhesion of monocytes to vascular endothelial cells via activation of the TLR4/NF-κB pathway. This potential new role for cTnI is clearly very novel and unexpected although additional roles for the protein were hinted at by its apparent localization at the membrane in the absence of other troponin subunits [4]. The precise mechanism by which this new function is mediated remains to be elucidated but the study suggests that inhibition of TLR4 may be a viable strategy to reduce cTnI-induced myocardial I/R injury.

FUNDING

This work was supported by the British Heart Foundation and the BHF Centre for Research Excellence, Oxford.

Abbreviations

     
  • cTnI

    cardiac troponin I

  •  
  • cTnT

    cardiac troponin T

  •  
  • DCM

    dilated cardiomyopathy

  •  
  • I/R

    ischaemia/reperfusion

  •  
  • NF-κB

    nuclear factor kappa beta

  •  
  • TLR4

    toll-like receptor 4

  •  
  • VCAM-1

    vascular cell adhesion molecule 1

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