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Injury of endothelial cells has been postulated to be an initial trigger of the progression of atherosclerosis in patients with diabetes. Previously, we demonstrated high D-glucose induced endothelial apoptosis through the bax-caspase pathway and the potential contribution of hepatocyte growth factor (HGF) to the pathogenesis of endothelial dysfunction. In this study, we analyzed the molecular mechanisms of the protective actions of HGF against endothelial cell death under high D-glucose conditions. High concentrations of D-glucose resulted in a significant increase in apoptosis and necrosis. In contrast, HGF attenuated high D-glucose-induced apoptosis and necrosis (P < 0.01). High D-glucose significantly increased bax protein, but not bcl-2, and activated caspase 3-like and 9, whereas HGF significantly increased bcl-2 expression without affecting bax level and attenuated the increase in caspase 3 and 9 activity. Interestingly, high D-glucose resulted in translocation of bax protein from cytosol to the mitochondrial membrane, whereas HGF inhibited the bax translocation. Importantly, this bax translocation was also completely blocked by overexpressed bcl-2. These findings suggest that HGF can activate bcl-2 expression and inhibit translocation of bax protein upstream of the mitochondria, thereby leading to the inhibition of caspase 3 and 9 activation. HGF may be an important factor in the maintenance of endothelial function., Dysfunction of endothelial cells is known to promote abnomal vascular growth such as that in atherosclerosis and arteriosclerosis (1). Diabetes is characterized by the premature development of microvascular and macrovascular [...]

Because high D-glucose significantly stimulates endothelial cell death, we examined the molecular mechanisms of high D-glucose-induced endothelial apoptosis. Treatment of human aortic endothelial cells with high D-glucose (25 mmol/l), but [...]

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Introduction:Despite the remarkable progress of medicine and endovascular procedures for revascularization, patients with critical limb ischemia (CLI) remain at high risk for amputation and often have a low quality of life due to pain and ulcers in the ischemic leg. Thus, a novel strategy for generating new blood vessels in CLI patients without treatment options is vital. Pre-clinical studies and Phase I clinical trials using VEGF and fibroblast growth factor (FGF) demonstrated promising results; however, more rigorous Phase II and III clinical trials failed to demonstrate benefits for CLI patients. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (Phase III) and the USA (Phase II) showed the benefits of hepatocyte growth factor (HGF) gene therapy for CLI patients. Although the number of patients included in these trials was relatively small, these results imply a distinct beneficial function for HGF over other angiogenic growth factors in a clinical setting.Areas covered:In this review, data from Phase I–III clinical trials of gene therapy for patients with peripheral artery disease (PAD) are examined. In addition, the potential mechanisms behind the success or failure of clinical trials are discussed.Expert opinion:Compared with VEGF and FGF, HGF has a unique molecular effect on inflammation, fibrosis and cell senescence under pathological conditions. These features may explain the clinical benefits of HGF in PAD patients.

Introduction:Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI.Areas covered:This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed.Expert opinion:To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects.

Peripheral artery disease (PAD) is caused by atherosclerosis, hardening and narrowing arteries over time due to buildup of fatty deposit in vascular bed called plaque. Severe blockage of an artery of the lower extremity markedly reduce blood flow, resulting in critical limb ischemia (CLI) manifested by a variety of clinical syndromes including rest pain in the feet or toes, ulcer and gangrene with infection. Despite significant advances in clinical care and interventions for revascularization, patients with CLI remain at high risk for amputation and cardiovascular death. To overcome this unmet need, therapeutic angiogenesis using angiogenic growth factors has evolved in an attempt to increase blood flow in ischemic limb. Initial animal studies and phase I clinical trials with vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) demonstrated promising results, inspiring scientists to progress forward. However, more rigorous phase II and III clinical trials have failed to demonstrate beneficial effects of these angiogenic growth factors to date. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (phase III) and US (phase II) demonstrated that hepatocyte growth factor (HGF) gene therapy for CLI significant improved primary end points and tissue oxygenation up to two years in comparison to placebo. These clinical results implicate a distinct action of HGF on cellular processes involved in vascular remodeling under pathological condition. This review presents data from phase I-III clinical trials of therapeutic angiogenesis by gene therapy in patients with PAD. Further, we discuss the potential explanation for the success or failure of clinical trials in the context of the biological mechanisms underlying angiogenesis and vascular remodeling, including cellular senescence, inflammation, and tissue fibrosis.

The mechanism of peripheral neuropathy has not been sufficiently clarified, and medical therapy for peripheral neuropathy is not established. Only a few reports have evaluated the analgesic effects of pregabalin in different diseases. In the present study, the effects of pregabalin in both orthopedic patients and surgical patients were compared, and the improvement of peripheral neuropathy was quantified. A questionnaire-based study was performed on numbness and the intensity of pain in orthopedic patients with organic diseases like spinal canal stenosis and in surgical patients with neuropathy from anti-cancer treatment. The data for patients who were prescribed pregabalin were examined using a numerical rating scale (NRS). Improvement of symptoms was observed in categories such as numbness, pain with numbness, and pain without numbness in orthopedic patients. NRS value decreased by 33 in all patients who were prescribed pregabalin. Drowsiness, a side effect of pregabalin, mostly disappeared over 4 weeks after pregabalin administration. Further, when combining drugs with pregabalin, the frequency of numbness and pain with numbness tended to be decreased by two agents (pregabalin NSAID), and was significantly decreased by three agents (pregabalin NSAID muscle relaxant), as compared with pregabalin-only treatment. The present study revealed the analgesic effect of pregabalin with regards to pain both with and without numbness. The data suggest that pregabalin is effective especially in orthopedic patients with organic injury of nerves.

Gene therapy offers a novel approach for the prevention and treatment of a variety of diseases, but it is not yet a common method in clinical cases because of various problems. Viral vectors show high efficiency of gene transfer, but they have some problems with toxicity and immunity. On the other hand, plasmid deoxyribonucleic acid (DNA)-based gene transfer is very safe, but its efficiency is relatively low. Especially, plasmid DNA gene therapy is used for cardiovascular disease because plasmid DNA transfer is possible for cardiac or skeletal muscle. Clinical angiogenic gene therapy using plasmid DNA gene transfer has been attempted in patients with peripheral artery disease, but a phase III clinical trial did not show sufficient efficiency. In this situation, more efficient plasmid DNA gene transfer is needed all over the world. This review focuses on plasmid DNA gene transfer and its enhancement, including ultrasound with microbubbles, electroporation, hydrodynamic method, gene gun, jet injection, cationic lipids and cationic polymers.

Novel therapeutic strategies using nucleic acid drugs, such as plasmid DNA (pDNA) and nuclear factor-B (NFB) decoy, have been sought for non-treatable neurological disorders. Among them, the application of pDNA has been extensively studied in diabetic neuropathy. Since growth factors, such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), have both neurotrophic and angiogenic properties, intramuscular injection of pDNA encoding these genes has been examined and shown to be effective for treatment in experimental animals and also in clinical trials. These growth factors have also been shown to accelerate neuroprotection, angiogenesis, and regeneration in the brain, and overexpression of these factors showed therapeutic effects in cerebral ischemia in rodents. Inhibition of inflammation is another strategy to treat cerebrovascular diseases. Recent studies suggest that NFB plays critical roles in the formation of cerebral aneurysms, and inhibition of its function by NFB decoy was shown to prevent cerebral aneurysm enlargement through inhibition of NFB-mediated inflammation. In the field of neurodegenerative disease, the potential of pDNA as a tool for vaccination has attracted researchers since pDNA itself has shown adjuvant properties and the potential to induce immunity or immune tolerance. pDNA encoding disease antigens, such as amyloid-A in Alzheimer disease or myelin basic protein in multiple sclerosis (MS), was shown to have therapeutic effects in rodents, and its efficacy and safety were reported in a phase I/II clinical study in MS. In this review, we discuss the potential and problems of nucleic acid drugs in neurological disorders.

Several types of Ca channel blockers (CCBs) which have unique organ protective effects are commercially available all over the world. However, the hypotensive and pleotropic effect in CCBs are not sufficiently assessed in the diabetic patient with refractory hypertension for angiotensin receptor blocker (ARB). We conducted a pilot study to compare the efficacy of two different CCBs (azelnidipine and nifedipine controlled release (CR)) in 55 hypertensive patients with type 2 diabetes who had not achieved their target blood pressure (BP) with ARB monotherapy. Patients were randomly assigned to receive azelnidipine (8–16 mg/day) or nifedipine CR (10–40 mg/day) concomitantly with valsartan (80 mg/day). There were no significant differences in baseline characteristics between the two groups. The final dose of azelnidipine and nifedipine CR was 13.3±3.9 and 17.1±9.4 mg/day, respectively. However the target BP (<130/80mmHg) achievement rate was higher in the earlier phase of the combination therapy with nifedipine CR than that of the azelnidipine group, the rates after 6 months were comparable between the groups (83 vs. 66). The systolic blood pressure was significantly lower in the nifedipine CR group from 2 to 6 months after the combination therapy (P<0.05, respectively). Both groups showed no significant changes in blood glucose and hemoglobin A1c. There were no significant differences in the urinary albumin/creatinine ratio and estimated Glomerular Filtration Rate (eGFR). In conclusion, the adjunctive therapy of nifedipine CR was superior to that of azelnidipine for decreasing blood pressure and achieving the target blood pressure, especially in the earlier phase of the diabetic patient with refractory hypertension for ARB. However the nephroprotective effect of nifedipine CR combination therapy was comparable to that of azelnidipine.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of morphogenic tissue interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed not only in hepatocyte but also in vascular cells, cardiac myocytes, skeletal muscle, kidney cells, neuronal cell, and fibroblasts. On the other hand, vascular endothelial growth factor (VEGF) is also a growth factor for endothelial cells. The signal transduction of VEGF and HGF is quite similar in physiological condition, but differs in pathological condition. To investigate this difference between HGF and VEGF, we showed that HGF but not VEGF prevents the senescence EPC due to oxidative stress through the inhibition of rac1. Moreover, we reported that HGF promotes SHIP-2 translocation from epithelial growth factor receptor (EGFR) to c-Met, and protects oxidative stress through EGFR degradation. By this anti-oxidative and anti-senescence effects of HGF would maintain the vessels long enough in patients receiving much oxidative stress. Another unique effect of HGF is anti-fibrosis. HGF does not inhibit TGF-1 in physiological condition, but reduces it in pathological, we discuss the potential effect of condition by promoting the myofibroblast apoptosis, and inhibits the vicious cycle of TGF-1 and angiotensin II through the inhibition of PTEN activity. In this report HGF on pathological condition in cardiovascular diseases and chronic kidney disease (CKD).

Although periostin, an extracellular matrix glycoprotein, plays pivotal roles in survival, migration, and regeneration in various cells, its expression and function in the brain are still unknown. Here, we investigated the expression and role of periostin in the ischemic brain.

Gene therapy offers a novel approach for the prevention and treatment of a variety of diseases, but it is not yet a common option in the real world because of various problems. Viral vectors show high efficiency of gene transfer, but they have some problems with toxicity and immunity. On the other hand, plasmid DNA-based gene transfer is very safe, but its efficiency is relatively low. Especially, plasmid DNA gene therapy is used for cardiovascular disease because plasmid DNA transfer is possible for cardiac or skeletal muscle. Clinical angiogenic gene therapy using plasmid DNA gene transfer has been attempted in patients with peripheral artery disease, but a Phase III clinical trial did not show sufficient efficiency. Recently, a Phase III clinical trial of hepatocyte growth factor gene therapy in peripheral artery disease (PAD) showed improvement of ischemic ulcers, but it could not salvage limbs from amputation. In addition, a Phase I/II clinical study of fibroblast growth factor gene therapy in PAD extended amputation-free survival, but it seemed to fail in Phase III. In this situation, we and others have developed plasmid DNA-based gene transfer using ultrasound with microbubbles to enhance its efficiency while maintaining safety. Ultrasound-mediated gene transfer has been reported to augment the gene transfer efficiency and select the target organ using cationic microbubble phospholipids which bind negatively charged DNA. Ultrasound with microbubblesis likely to create new therapeutic options inavariety of diseases.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator for morphogenic tissue interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed in vascular cells and cardiac myocytes. On the other hand, recently, we demonstrated that HGF plasmid DNA transfer significantly improves the size of ulcer in patients with peripheral artery disease (PAD) at Phase III clinical trial, while vascular endothelial growth factor (VEGF) gene therapies for PAD at Phase III have not been succeeded yet. To further investigate this difference between HGF and VEGF, we showed that HGF but not VEGF improves the senescence EPC against oxidative stress through the inhibition of rac1. Moreover, we reported that HGF promotes SHIP-2 translocation from epithelial growth factor receptor (EGFR) to c-Met, and it would protect oxidative stress through EGFR degradation. By this anti-oxidative and anti-senescence effects of HGF would maintain the vessel so long in patients with PAD who receive much oxidative stress in real world. In this report, we discuss a potential therapeutic strategy using HGF in cardiovascular diseases.

The progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA-positive myofibroblasts producing large amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Although hepatocyte growth factor (HGF) improved renal fibrosis in various models, the molecular mechanisms involved are not yet fully understood.

In this study, we investigated the role of hepatocyte growth factor (HGF) in blood formation during Xenopus development. First, we examined the gene expression of HGF and its receptor, c-met, by whole-mount in situ hybridization during development. Strong signals of HGF as well as c-met were detected early in the developing ventral mesoderm, which later gives rise to the ventral blood island. Furthermore, to study the role of HGF, we blocked the HGF signaling pathway in Xenopus embryos by using truncated c-met lacking the tyrosine kinase domain. Injection of truncated c-met mRNA resulted in a marked decrease in the number of circulating blood cells. Similar results were obtained using morpholino antisense HGF oligonucleotides. Moreover, we also analyzed the expression of several early primitive blood markers in the blood island of these embryos. RNA in situ analysis revealed a significant reduction (or absence) of stem cell leukemia (SCL), α-globin, and GATA-1 expression, but not GATA-2 expression. In contrast, no significant difference was observed in the levels of expression of early definitive blood markers, SCL, GATA-2, and GATA-3 in the dorsolateral plate, as analyzed by in situ hybridization. Overall, the present study demonstrated that HGF is necessary for primitive hematopoiesis by regulating the expression of SCL. (Blood. 2004;103:3320-3325)

OBJECTIVES

To investigate the molecular mechanisms of the anti-apoptotic action of hepatocyte growth factor (HGF), a novel angiogenic growth factor that may have a pivotal role in the regulation of endothelial cells, on human aortic endothelial cells.

OBJECTIVES

AbstractGene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, homozygous familial hypercholesterolemia and cystic fibrosis, for which no known effective therapy exists. Gene therapy requires efficient in vivogene transfer technology. During the past decade, many gene transfer methods including viral transfer techniques have been developed, and some are being applied clinically in human gene therapy studies. Molecular biology and pathophysiology of the cardiovascular system have started to emerge, and the time is ripe for the introduction of gene therapy to the management of cardiovascular disorders. In this review, we have focused on the future potential of oligonucleotide-based gene therapy for the treatment of cardiovascular disease.

Objectives. We assessed the acute effect of intracoronary injection of verapamil on microvascular function after primary percutaneous translumanal coronary angioplasty (PTCA) for acute myocardial infarction (AMI) with myocardial contrast echocardiography (MCE) in relation to functional outcomes.

Lipoprotein(a) (Lp(a)) is an independent risk factor for atherosclerosis. Effective therapy for treating Lp(a)-induced CVD has yet to be developed. Angiotensin II type1 receptor (AT1R) blockers have known beneficial effects in improving atherosclerosis, beyond mere blood pressure reduction. Thus, ARBs may improve even Lp(a)-induced atherosclerosis.

We comparatively studied the combined effects of 2 types of calcium channel blocker (CCB) (Azelnidipine tablet: AZL, Nifedipine CR tablet: NCR) in hypertensive patients with diabetes who have failed to achieve target blood pressure levels by usual dose of angiotensin II receptor antagonist (ARB).

Serotonin (5-HT) plays a crucial role in pathological conditions of peripheral artery disease (PAD) and diabetes mellitus (DM). In these conditions, the balance between the 5-HT2A receptor in smooth muscle cells and the 5-HT1B receptor in endothelial cells (EC) regulates vascular tonus. In the present study, we focused on the role of 5-HT in endothelial dysfunction using a selective 5-HT2A receptor blocker, sarpogrelate.

Irbesartan and telmisartan are Angiotensin (Ang) II type 1 receptor (AT1R) blockers (ARBs) with perioxisome-proliferator activated receptor (PPAR) agonistic effects, which mediate organ protective effects independent of their AT1R blockade. Irbesaratan has especially strong cardiac and renal protective effects. Telmisartan reduces renal fibrosis and inflammation by inducing hepatocyte growth factor (HGF) expression, independently of AT1aR blockade in unilateral ureteral obstruction (UUO) models created in AT1aR knockout mice (AT1aR-KO). Here we test whether or not irbesartan exerts organ protective effects in mouse models of salt sensitive hypertension.

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