Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating vasogenic factors may be up-regulated in response to ischemia to promote angiogenesis in patients with peripheral artery disease (PAD). Studies on this are limited in number and size, and results are inconsistent, especially regarding basic fibroblast growth factor (bFGF) level. From March 1999 to April 2004, all consecutive patients with lower limb PAD having serum samples at the time of intervention were recruited. The diameter of the primary PAD lesion had to be at least 70% stenotic at the lower limb artery. Control subjects, who underwent angiography, were free of PAD, coronary disease, and other major medical diseases. Serum samples were analyzed for circulating hepatocyte growth factor (HGF) and bFGF levels. Patients with PAD (n = 60) had higher circulating HGF levels (mean +/- SEM, 1,544 +/- 238 vs 970 +/- 129 pg/mL; P = .04) but similar bFGF distribution tertiles (P = .55) compared with control subjects (n = 30). Thirty-six patients with summed PAD lesion lengths exceeding 5 cm demonstrated a significantly higher circulating HGF level compared with control subjects (mean +/- SEM, 1,701 +/- 335 vs 970 +/- 129 pg/mL; P = .048). Patients with concurrent coronary artery disease tend to have a higher circulating HGF level (mean +/- SEM, 1,606 +/- 365 vs 970 +/- 129 pg/mL; P = .06) but not a higher bFGF level compared with control subjects. Circulating HGF level, but not bFGF level, is significantly elevated in patients with symptomatic angiographically documented PAD, especially in those with more extensive involvement.
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PMID:Circulating hepatocyte growth factor level but not basic fibroblast growth factor level is elevated in angiography-proven symptomatic peripheral artery disease. 1787 55

The use of adipose-derived stem/stromal cells (ASCs) for promoting repair of tissues is a promising potential therapy, but the mechanisms of their action are not fully understood. We and others previously demonstrated accelerated reperfusion and tissue salvage by ASCs in peripheral ischemia models and have shown that ASCs secrete physiologically relevant levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor. The specific contribution of HGF to ASC potency was determined by silencing HGF expression. RNA interference was used to downregulate HGF expression. A dual-cassette lentiviral construct expressing green fluorescent protein (GFP) and either a small hairpin RNA specifically targeted to HGF mRNA (shHGF) or an inactive control sequence (shCtrl) were used to stably transduce ASCs (ASC-shHGF and ASC-shCtrl, respectively). Transduced ASC-shHGF secreted >80% less HGF, which led to a reduced ability to promote survival, proliferation, and migration of mature and progenitor endothelial cells in vitro. ASC-shHGF were also significantly impaired, compared with ASC-shCtrl, in their ability to promote reperfusion in a mouse hindlimb ischemia model. The diminished ability of ASCs with silenced HGF to promote reperfusion of ischemic tissues was reflected by reduced densities of capillaries in reperfused tissues. In addition, fewer GFP(+) cells were detected at 3 weeks in ischemic limbs of mice treated with ASC-shHGF compared with those treated with ASC-shCtrl. These results indicate that production of HGF is important for the potency of ASCs. This finding directly supports the emerging concept that local factor secretion by donor cells is a key element of cell-based therapies. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. 1790

Cerebral ischemia causes an irreversible and neurodegenerative disorder that may lead to progressive dementia and global cognitive deterioration. Since the overall process of ischemic brain injuries is extremely complex, treatment with endogenous multifunctional factors would be better choices for preventing complicated ischemic brain injuries. Hepatocyte growth factor, HGF, is a multifunctional cytokine originally identified and purified as a potent mitogen for hepatocyte. The activation of the c-Met/HGF receptor evokes diverse cellular responses, including mitogenic, morphogenic, angiogenic and anti-apoptotic activities in various types of cell. Previous studies showed that HGF and c-Met were expressed in various brain regions under normal conditions and that HGF enhanced the survival of hippocampal and cortical neurons during the aging of cells in culture. The protective effects of HGF on in vivo ischemic brain injuries and their mechanisms have not fully understood. To elucidate therapeutic potencies of HGF for ischemic brain injuries, we examined effects of HGF on ischemia-induced learning and memory dysfunction, neuronal cell death and endothelial cell damage by using the 4-vessel occlusion model and the microsphere embolism model in rats. Our findings suggested that treatment with HGF was capable of protecting hippocampal neurons against ischemia-induced cell death through the prevention of apoptosis-inducing factor translocation to the nucleus. Furthermore, we demonstrated that HGF had the ability to prevent tissue degeneration and improved learning and memory function after cerebral embolism, possibly through prevention of cerebral vessel injuries. As HGF has a potent cerebroprotective effect, it could be a prospective agent for the therapy against complicated ischemic brain diseases.
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PMID:[Ischemic brain injury and hepatocyte growth factor]. 1797 57

We determined change in serum hepatocyte growth factor (HGF), one of the most potent angiogenic factors, after intravenous infusion of heparin in children and reported successful improvement of cardiac ischemia after regular intravenous heparin infusion in an infant with ischemic heart disease (IHD) caused by Kawasaki disease (KD). Intravenous infusion of 50 units/kg of heparin significantly increased serum HGF from 0.8+/-0.6 to 8.4+/-3.4 at 5 min, 8.3+/-2.5 at 30 min, and 4.9+/-1.5 ng/ml at 60 min, respectively. Subsequently, a 16-month-old infant with IHD caused by KD had received regular intravenous infusion of heparin, 100 IU/kg twice a day for 1 month and once a week for subsequent 2 months. With this treatment, his perfusion defect on myocardial scintigraphy disappeared. In conclusion, regular heparin infusion alone can improve myocardial ischemia caused by KD, probably due to facilitated production of HGF.
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PMID:Intermittent heparin infusion in children with ischemic heart disease caused by Kawasaki disease. 1824 69

The production of growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by human bone marrow mesenchymal stem cells (MSCs) may play an important role in their paracrine effects on proliferation, differentiation, and protection. NO is produced during ischemia and may affect MSC function. However, it is unknown whether NO alters the production of VEGF and HGF from MSCs. To study this, human MSCs were stimulated to produce growth factors with TNF or LPS with and without various doses of NO donors or NOS inhibitors. We found that FK409, an NO donor, significantly suppressed the production of VEGF and HGF from human MSCs. Vascular endothelial growth factor in the supernatants of cells treated by 20 nM FK409 (497 +/- 19 pg/mL) was significantly lower compared with controls (625 +/- 34 pg/mL). Similarly, NO donor significantly suppressed the amount of HGF from controls (118 +/- 3 to 40 +/- 2 pg/mL) after treatment with 20 nM FK409. NO donor also abolished the augmentation of VEGF production induced by LPS. The amount of VEGF in the supernatant was 571 +/- 11 pg/mL when cells were treated with 20 nM FK409 and LPS (200 ng/mL), which was significantly lower than groups treated with LPS alone (941 +/- 30 pg/mL). This study constitutes an initial report regarding the effect of NO on human MSC growth factor production.
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PMID:Nitric oxide suppresses the secretion of vascular endothelial growth factor and hepatocyte growth factor from human mesenchymal stem cells. 1839 52

Mesenchymal stem cells (MSC) are adult multipotent cells found in bone marrow, adipose tissue, and other adult tissues. MSC have been shown to improve regeneration of injured tissues in vivo, but the mechanisms remain unclear. Typically, MSC are cultured under ambient, or normoxic, conditions (21% oxygen). However, the physiological niches for MSC in the bone marrow and other sites have much lower oxygen tension. When used as a therapeutic tool to repair tissue injuries, MSC cultured in standard conditions must adapt from 21% oxygen in culture to less than 1% oxygen in the ischemic tissue. We therefore examined the effects of preculturing human bone marrow-derived MSC in hypoxic conditions (1%-3% oxygen) to elucidate the best conditions that enhance their tissue regenerative potential. We demonstrated that MSC cultured in hypoxia activate the Akt signaling pathway while maintaining their viability and cell cycle rates. We also showed that MSC cultured in hypoxia induced expression of cMet, the major receptor for hepatocyte growth factor (HGF), and enhanced cMet signaling. MSC cultured in hypoxic conditions increased their migration rates. Since migration and HGF responsiveness are thought to be key mediators of MSC recruitment and/or activation in vivo, we next examined the tissue regenerative potential of MSC cultured under hypoxic conditions, using a murine hind limb ischemia model. We showed that local expression of HGF is increased in ischemic muscle in this model. Intra-arterial injection of MSC cultured in either normoxic or hypoxic conditions 24 hours after surgical induction of hind limb ischemia enhanced revascularization compared with saline controls. However, restoration of blood flow was observed significantly earlier in mice that had been injected with hypoxic preconditioned MSC. Collectively, these data suggest that preculturing MSC under hypoxic conditions prior to transplantation improves their tissue regenerative potential. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. 1851 1

Coronary artery and peripheral vascular disease are global health concerns with limited therapies. Currently available medical and surgical therapies for these disease processes are highly effective for only a fraction of patients. Extensive effort has been devoted to finding molecular therapies to enhance perfusion and function of ischemic myocardial and peripheral skeletal muscle. Angiogenic cytokines (fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], placental growth factor, stromal cell-derived factor-1alpha) have shown theoretical and experimental promise in upregulating endogenous endothelial progenitor cell-mediated angiogenesis. Preliminary clinical trials have suggested improvements in myocardial and peripheral perfusion following therapy with FGF, VEGF, and HGF. Further studies on the efficacy of cytokine-mediated angiogenesis are required before widespread clinical application is possible. Investigation into adjunctive cytokine therapies for myocardial and peripheral muscle ischemia is warranted. Based on experimental evidence, appropriate angiogenic cytokine therapy should provide benefits in both perfusion and hemodynamic function.
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PMID:Pro-angiogenic cytokines as cardiovascular therapeutics: assessing the potential. 1861 Oct 64

Bone marrow-derived mesenchymal stem cells (BM-MSC) have been demonstrated to be an attractive therapeutic cell source for tissue regeneration and repair. However, it remains unknown whether or not allogeneic transplantation of mesenchymal stem cells (MSC) derived from fetal membranes (FM), which are generally discarded as medical waste after delivery, has therapeutic potential. FM-MSC were obtained from Lewis rats and had surface antigen expression and multipotent potential partly similar to those of BM-MSC. Compared with BM-MSC, FM-MSC secreted a comparable amount of hepatocyte growth factor despite a small amount of vascular endothelial growth factor. FM-MSC and BM-MSC both expressed major histocompatibility complex (MHC) class I but not MHC class II antigens and did not elicit allogeneic lymphocyte proliferation in mixed lymphocyte culture. FM-MSC or BM-MSC obtained from Lewis rats were injected into a MHC-mismatched August-Copenhagen-Irish rat model of hind limb ischemia. Three weeks after injection, blood perfusion and capillary density were significantly higher in the FM-MSC and BM-MSC groups than in the phosphate-buffered saline group, and allogeneic FM-MSC and BM-MSC were still observed. In nonischemic hind limb tissues, allogeneic FM-MSC and BM-MSC injection were associated with a comparatively small amount of T lymphocyte infiltration, compared with the injection of allogeneic splenic lymphocytes. In conclusion, allogeneic FM-MSC injection did not elicit a lymphocyte proliferative response and provided significant improvement in a rat model of hind limb ischemia, comparable to the response to BM-MSC. Thus, allogeneic injection of FM-MSC may be a new therapeutic strategy for the treatment of severe peripheral vascular disease. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia. 1866 10

Adipose-derived stem/stromal cells (ASCs) not only function as tissue-specific progenitor cells but also are multipotent and secrete angiogenic growth factors, such as hepatocyte growth factor (HGF), under certain circumstances. However, the biological role and regulatory mechanism of this secretion have not been well studied. We focused on the role of ASCs in the process of adipose tissue injury and repair and found that among injury-associated growth factors, fibroblast growth factor-2 (FGF-2) strongly promoted ASC proliferation and HGF secretion through a c-Jun N-terminal kinase (JNK) signaling pathway. In a mouse model of ischemia-reperfusion injury of adipose tissue, regenerative changes following necrotic and apoptotic changes were seen for 2 weeks. Acute release of FGF-2 by injured adipose tissue was followed by upregulation of HGF. During the adipose tissue remodeling process, adipose-derived 5-bromo-2-deoxyuridine-positive cells were shown to be ASCs (CD31-CD34+). Inhibition of JNK signaling inhibited the activation of ASCs and delayed the remodeling process. In addition, inhibition of FGF-2 or JNK signaling prevented postinjury upregulation of HGF and led to increased fibrogenesis in the injured adipose tissue. Increased fibrogenesis also followed the administration of a neutralizing antibody against HGF. FGF-2 released from injured tissue acts through a JNK signaling pathway to stimulate ASCs to proliferate and secrete HGF, contributing to the regeneration of adipose tissue and suppression of fibrogenesis after injury. This study revealed a functional role for ASCs in the response to injury and provides new insight into the therapeutic potential of ASCs.
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PMID:IFATS collection: Fibroblast growth factor-2-induced hepatocyte growth factor secretion by adipose-derived stromal cells inhibits postinjury fibrogenesis through a c-Jun N-terminal kinase-dependent mechanism. 1877 14

Hepatocyte growth factor (HGF) is known to promote renal epithelial cell survival by dual mechanisms involving Bad phosphorylation and Bcl-xL induction. However, it remains elusive as to the relative contributions of these two events to HGF-mediated cytoprotection. Here we investigated the role and mechanism of HGF in protecting renal epithelial cells from death induced by oxidant stress both in vitro and in vivo. Simultaneous incubation of human kidney proximal tubular epithelial cells (HKC-8) with HGF failed to protect them from oxidant stress-induced cell death, even though it was capable of inducing endogenous Akt and Bad phosphorylation. However, pre-incubation of HKC-8 cells with HGF for 48 hours dramatically promoted their survival and prevented caspase-3 cleavage and activation induced by H(2)O(2). A close association between Bcl-xL induction and effective cytoprotection by HGF was observed in HKC-8 cells after H(2)O(2) treatment. Furthermore, ectopic expression of exogenous Bcl-xL via adenoviral vector prevented H(2)O(2)-triggered caspase-3 activation. In a mouse model of acute kidney injury induced by ischemia/reperfusion, pre-administration of HGF expression vector drastically prevented apoptosis and largely preserved kidney function, whereas much less protective effect was observed when HGF gene was given immediately after ischemic injury. These results suggest that Bcl-xL induction plays an imperative role in mediating HGF cytoprotection of renal epithelial cells after death challenge.
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PMID:Role of Bcl-xL induction in HGF-mediated renal epithelial cell survival after oxidant stress. 1878 16


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