The Role of the Thrombospondins in Healing Myocardial Infarcts

Abstract

The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.

The immune system and cardiac repair

“…Our findings suggested that the selective endogenous expression of TSP-1 in the infarct border zone may protect the non-infarcted myocardium from inflammatory cell infiltration and fibrotic remodeling. Several distinct TSP-1-mediated actions may be responsible for its protective effects [332]. First, enhanced TGF-β activation in the border zone may locally suppress inflammatory mediator synthesis.…”

Identification of nondiabetic heart failure-associated genes by bioinformatics approaches in patients with dilated ischemic cardiomyopathy

“…Therefore, it is no surprise that CD44, which is involved in the ECM-receptor interaction, was found to be downregulated in the current study. Chatila et al (38) also found that certain compositions of the infarct border zone may slow down left ventricular remodeling by suppressing inflammation. In the current study, GO terms enriched by downregulated genes were mainly associated with the stimulus and immune response.…”

TIMPs and cardiac remodeling: ‘Embracing the MMP-independent-side of the family’

“…For example, low-density lipoprotein receptor-related protein (LRP) is a versatile scavenger and signaling receptor that binds multiple unrelated ligands and influences a wide variety of biological processes (reviewed by Lillis et al [58]). Since TIMP1 and -2, either alone or complexed with proMMP-2 or -9, respectively, can interact with LRP, it will be of particular interest to investigate whether LRP represents (i) a 'mitogenic' receptor for TIMPs; as it is the 'motogenic' receptor for plasminogen activator inhibitor-1 [59], and/ [58,60,61]. LRP is able to bind thrombospondin-1 and -2, two matricellular proteins that seem to be crucial regulators of the cardiac integrity necessary for the myocardium to cope with increased loading or ischemic stress [60,61].…”

“…Since TIMP1 and -2, either alone or complexed with proMMP-2 or -9, respectively, can interact with LRP, it will be of particular interest to investigate whether LRP represents (i) a 'mitogenic' receptor for TIMPs; as it is the 'motogenic' receptor for plasminogen activator inhibitor-1 [59], and/ [58,60,61]. LRP is able to bind thrombospondin-1 and -2, two matricellular proteins that seem to be crucial regulators of the cardiac integrity necessary for the myocardium to cope with increased loading or ischemic stress [60,61]. Interestingly, the proMMP-2/TIMP-2/thrombospondin-triplex can be scavenged via LRP-mediated endocytosis, regulating the levels of both MMP-2 and TIMP-2 in the extracellular cardiac matrix.…”