Chapter 6 - Tissue transglutaminase enzyme and anti-tissue transglutaminase antibodies: implication for acute coronary syndrome

The type II or tissue transglutaminase (TG2) is an ubiquitous enzyme involved in angiogenesis, fibrogenesis, wound healing, cell adhesion/migration, intracellular signaling pathways, respiratory chain assembly, cell proliferation/differentiation, neurite formation, apoptosis, and inflammation. Some years ago, an increased extracellular localization of TG2 has been demonstrated in damaged or inflamed portions of the small intestine from patients with celiac disease (CD). This antigenic overexpression is able to explain, at least in part, the anti-TG2 antibody induction observable in CD patients. On the other hand, anti-TG2 antibodies have been recently described in patients affected from disorders in which the target organ is located at a distance from the intestine, such as acute coronary syndrome (ACS), dilated cardiomyopathy (DCM), valvular heart disease and other causes of end-stage heart failure. In this regard, a cardiac TG2 overexpression has been described in some experimental models of heart failure and in occurrence of myocardial ischemia/reperfusion injury. In the arteries with or without minimal atherosclerosis, TG2 is detectable only in the medium and along the luminal endothelial border while in the atherosclerotic arteries, especially coronaries and carotid vessels, this enzyme is also evident in the fibrous cup and in shoulder regions of the plaque. Consequently, an anti-TG2 antibody-inducing mechanism similar to those taking part in the intestine of CD patients may also occur in the cardiovascular tissues affected from an acute or chronic disorder. Consistent with this hypothesis, anti-TG2 antibodies seem to be related to severity of the acute coronary event, as well as to extent of the myocardial tissue lesion occurring in ACS patients. Furthermore, since TG2 enzymatic activity may result in myocardial wound healing and stabilization of atherosclerotic plaque, anti-TG2 antibodies could have biological effects able to define a prognostic significance. In this light, vulnerable or ruptured atherosclerotic plaque, as well as injured myocardium (following an infarction, myocarditis, etc.) may be sources of TG2 antigen resulting in formation of anti-TG2 antibodies that in turn, by neutralizing TG2 enzymatic activity, could promote destabilization of the plaque or impaired myocardial wound healing, thereby contributing to a chronic disorder such as DCM. The finding that anti-TG2 antibodies are able to induce proliferation and inhibit differentiation of intestinal epithelial cell, increase epithelial permeability, activate monocytes, and disturb angiogenesis in CD patients suggests that they may have a functional role also in cardiovascular disorders. In the near future, these observations and related hypothesis could to become the subject of interesting researches.