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【medical-news】血管抑素：枯竭心肌细胞的根源
Stem and progenitor cells are promising new treatment options to enhance muscular growth and restore cardiac ventricular function in diseased heart. To date, many cell types from different sources (embryonic, bone marrow, induced pluripotent, endogenous cardiac stem cells, mesenchymal stem cells) have been used with a perspective to restore cardiac muscle after myocardial infarction and to enhance cardiac function.1 This has resulted in several studies approaching the feasibility and experimental as well as clinical benefit of modifying cardiac function by cytotherapy. Although, in clinical trials, data on long-term effects of cell transplantation in hearts with myocardial infarction are still missing, and potential side effects like generation of arrhythmias and restricted cardiac growth can still not be excluded, some of the trials both in clinical and in experimental settings have promising results regarding the partial restoration of ejection fraction after myocardial infarction.2 3 However, it remains unclear whether stem or progenitor cells contribute directly to recovery processes in failing hearts by integrating into the heart tissue and participating in contraction. Thus, it was shown that after myocardial infarction, only poor engraftment is achieved, utilising mononuclear and mesenchymal bone marrow cells.4 Rather, paracrine or humoral factors may play a role in the homing and linkage of transplanted cells to cardiac muscle or fibrous scar tissue after myocardial infarction or in heart failure.5
Angiostatin has been shown to inhibit vascular growth in a variety of tissues. Angiostatin is a proteolytic fragment of plasminogen which is released by metalloproteinase type II and IX.6 It inhibits endothelial cell proliferation7 and induces apoptosis.8 Due to its vascular inhibitory potential, it has attracted attention especially in oncological research in order to reduce vascular growth in cancer tissue and inhibit potential tumour growth progression.9 Thus, in cancer tissue, angiostatin may be beneficial in inhibiting vascular proliferation in the proximity to tumours. Oncological phase 1 trials are ongoing to explore the clinical utility of this vascular inhibition.10
In cardiac tissues, angiostatin has caused attention in the area of vascular growth progression in infarcted hearts. Knowledge of cardiac tissue is limited to an extent that only a few studies have shown that angiostatin has a potential to influence vascular growth in heart cells. Although growth factors may be useful in underperfused or infarcted myocardial tissue, such as hibernating, stunning or infarcted tissue, angiostatin has not been yet identified in heart failure to contribute to the progression of the disease. While other areas of research in heart failure, such as the calcium homeostasis11 or dysfunction of the myofilaments12 are better defined, the role of angiostatin in heart failure has not been described.
In the current issue of Heart, Yamahara et al13 utiltised mesenchymal stem cells (MSC) to study the role of angiostatin in the development of heart failure. Angiostatin was upregulated in sera from a subset of heart failure patients due to dilated cardiomyopathy, while no changes were seen in ischaemic cardiomyopathy (see page 283). These sera inhibited the proliferation of cultured MSC. As one potential inhibitory protein, angiostatin was identified utilising a protein array chip. Usually this fairly novel technique results in a bundle of new factors that may influence a disease state or pathological condition. However, studies using a protein arrays approach often lack a clear-cut description as to which of those identified factors are only secondary or compensatory and really contribute to deterioration or improvement of a disease state. Likewise, it often remains unclear and speculative how the identified factors or modifiers really result in functional or dysfunctional consequences.
Yamahara et al13 were able to show increased angiostatin levels in only two heart-failure patients’ sera; other samples obtained from patients with dilated cardiomyopathy (DCM) or ischaemic cardiomyopathy (ICM) did not reveal increased abundance of angiostatin indicating that only a subset of patients with DCM display this pattern of upregulation. Thus, the upregulation of angiostatin is not a response that occurs in general in dilated cardiomyopathy, but rather a diverse regulatory response underlining the diversity of this disease. Moreover, the authors studied expression and cleavage of angiostatin to metalloproteinase subtype IX and showed similar results in upregulation seen for total angiostatin expression. Likewise, migration of cultured MSC was inhibited, and apoptosis was increased in angiostatin-treated cell cultures. In addition, the authors used a heart-failure postmyocarditis rat model (utilising Mycobacterium tuberculosis as a reagent) to further evaluate the in vivo effects on cardiac function of angiostatin and metalloproteinase subtype IX (the activator of angiostatin). The authors found increased angiostatin levels in this animal heart-failure model. Moreover, decreased cardiac output was prevented by treating these animals with an inhibitor of metalloproteinase subtype IX, which prevented angiostatin release.
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作者:admin@医学,生命科学 2011-02-23 05:11
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