Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic ...fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family 7 member 11 (Slc7a11), ferritin heavy chain 1 (Fth1), ferritin light chain 1 (Ftl1), and solute carrier family 40 member 1 (Slc40a1). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that Bach1−/− mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:We are now facing rapid population aging in Japan, which will affect the actual situation of cardiovascular diseases. However, age-specific trends in the incidence and mortality of acute ...myocardial infarction (AMI) in Japan remain to be elucidated.Methods and Results:We enrolled a total of 27,220 AMI patients (male/female 19,818/7,402) in our Miyagi AMI Registry during the past 30 years. We divided them into 4 age groups (≤59, 60–69, 70–79 and ≥80 years) and examined the temporal trends in the incidence and in-hospital mortality of AMI during 3 decades (1985–1994, 1995–2004 and 2005–2014). Throughout the entire period, the incidence of AMI steadily increased in the younger group (≤59 years in both sexes), while in the elderly groups (≥70 years in both sexes), the incidence significantly decreased during the last decade (all P<0.01). In-hospital cardiac mortality significantly decreased during the first 2 decades in elderly groups of both sexes (all P<0.01), whereas no further improvement was noted in the last decade irrespective of age or sex, despite improved critical care of AMI.Conclusions:These results provide the novel findings that the incidence of AMI has been increasing in younger populations and decreasing in the elderly, and that improvement in the in-hospital mortality of AMI may have reached a plateau in all age groups in Japan.
Since the treatment window of thrombolytic therapy for stroke is limited, new therapy remains to be developed. We have recently developed low-intensity pulsed ultrasound (LIPUS) therapy to improve ...cognitive dysfunction in mouse models of vascular dementia and Alzheimer's disease. Here, we further aimed to examine whether our LIPUS therapy improves neurological recovery from ischemic stroke, and if so, to elucidate the mechanisms involved. In a mouse model of middle cerebral artery occlusion (MCAO), we applied LIPUS (32 cycles, 193 mW/cm
) to the whole brain 3 times in the first week (days 1, 3, and 5) after MCAO. We evaluated neurological functions using behavioral tests and performed histological analyses. Furthermore, to elucidate how LIPUS works within the injured brain, we also tested the effects of LIPUS in endothelial nitric oxide synthase (eNOS)-deficient (eNOS
) mice. In wild-type mice, the LIPUS therapy markedly improved neurological functions in the tightrope and rotarod tests at 28 days after MCAO. Histological analyses showed that the LIPUS therapy significantly increased the numbers of CD31-positive blood vessels in the perifocal lesion and doublecortin (DCX)-positive neurons in the ischemic striatum, indicating the angio-neurogenesis effects of the therapy. Importantly, these beneficial effects of the LIPUS therapy were totally absent in eNOS
mice. No adverse effects of the LIPUS therapy were noted. These results indicate that the LIPUS therapy improves neurological functions after stroke through enhanced neuro-angiogenesis in mice in vivo in an eNOS-dependent manner, suggesting that it could a novel and non-invasive therapeutic option for stroke.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Along with the progress of global aging, the prognosis of severe ischemic heart disease (IHD) remains poor, and thus the development of effective angiogenic therapy remains an important clinical ...unmet need. We have developed low-energy extracorporeal cardiac shock wave therapy as an innovative minimally invasive angiogenic therapy and confirmed its efficacy in a porcine chronic myocardial ischemia model in animal experiments as well as in patients with refractory angina. Since ultrasound is more advantageous for clinical application than shock waves, we then aimed to develop ultrasound therapy for IHD. We demonstrated that specific conditions of low-intensity pulsed ultrasound (LIPUS) therapy improve myocardial ischemia in animal models through the enhancement of angiogenesis mediated by endothelial mechanotransduction. To examine the effectiveness of our LIPUS therapy in patients with severe angina pectoris, we are now conducting a prospective multicenter clinical trial in Japan. Furthermore, to overcome the current serious situation of dementia pandemic but with no effective treatments worldwide, we have recently demonstrated that our LIPUS therapy also improves cognitive impairment in mouse models of Alzheimer’s disease and vascular dementia. Here, we summarize the progress in our studies to develop angiogenic therapies with sound waves.
We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia through enhanced myocardial angiogenesis in a porcine model of chronic ...myocardial ischemia and in patients with refractory angina pectoris. However, the detailed molecular mechanisms for the SW-induced angiogenesis remain unclear. In this study, we thus examined the effects of SW irradiation on intracellular signaling pathways in vitro. Cultured human umbilical vein endothelial cells (HUVECs) were treated with 800 shots of low-energy SW (1 Hz at an energy level of 0.03 mJ/mm(2)). The SW therapy significantly upregulated mRNA expression and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The SW therapy also enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt. Furthermore, the SW therapy enhanced phosphorylation of caveolin-1 and the expression of HUTS-4 that represents β1-integrin activity. These results suggest that caveolin-1 and β1-integrin are involved in the SW-induced activation of angiogenic signaling pathways. To further examine the signaling pathways involved in the SW-induced angiogenesis, HUVECs were transfected with siRNA of either β1-integrin or caveolin-1. Knockdown of either caveolin-1 or β1-integrin suppressed the SW-induced phosphorylation of Erk1/2 and Akt and upregulation of VEGF and eNOS. Knockdown of either caveolin-1 or β1-integrin also suppressed SW-induced enhancement of HUVEC migration in scratch assay. These results suggest that activation of mechanosensors on cell membranes, such as caveolin-1 and β1-integrin, and subsequent phosphorylation of Erk and Akt may play pivotal roles in the SW-induced angiogenesis.
Low-energy extracorporeal shock waves (LESW) have been studied as a new treatment for angina pectoris and several ischemic diseases because of its effect on angiogenesis and inhibition of fibrosis of ...the heart. The effect of LESW on fibrosis in liver cirrhosis has not been studied. The aim of this study was to verify the amelioration of liver fibrosis by LESW and elucidate its mechanisms in a rat model of drug-induced liver cirrhosis. Male Wistar rats aged 7 weeks were injected with carbon tetrachloride intraperitoneally twice a week for 12 weeks. Eight rats underwent LESW therapy (0.25 mJ/mm
, 4 Hz, 1000 shots) under general anesthesia (shock wave group). Seven rats only underwent general anesthesia (control group). Quantitative analysis showed that the area of fibrosis in the shock wave group was significantly reduced compared with the control group (11,899.9 vs. 23,525.3 pixels per field, p < 0.001). In the shock wave group, the mRNA expression of transforming growth factor (TGF)-β1 was significantly suppressed (0.40-fold, p = 0.018) and vascular endothelial growth factor-B was significantly increased (1.77-fold, p = 0.006) compared with the control group. Serum albumin was significantly higher in the shock wave group than in the control group (3.0 vs. 2.4 g/dl, p = 0.025). Aspartate aminotransferase/alanine aminotransferase ratio decreased by LESW compared with the control group (1.49 vs. 2.04, p = 0.013). These results suggest that LESW therapy ameliorates liver fibrosis by reducing the expression of TGF-β1 and increasing the expression of angiogenic factors, and improves hepatic function.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ...ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved.
We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain.
In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice.
These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.
•The whole-brain LIPUS is an effective and safe in two mouse models of dementia.•LIPUS enhanced angio- and OPC-genesis in a mouse model of vascular dementia.•LIPUS enhanced angiogenesis and reduced Aβ in a mouse model of Alzheimer disease.•eNOS plays a key role in the beneficial effects of LIPUS in both mouse models.•LIPUS therapy to the whole brain may be a new strategy for dementia in humans.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Low-energy extracorporeal shock wave therapy (ESWT) has been used to treat various human diseases. Previous studies have shown that low-energy ESWT promotes the release of various cell growth factors ...and trophic factors from the cells surrounding the target lesion. The aim of the current study was to determine whether the application of low-energy ESWT upregulates the expression of brain-derived neurotrophic factor (BDNF) and reduces neural tissue damage and functional impairment using a rat model of thoracic spinal cord contusion injury. We found that low-energy ESWT promoted BDNF expression in the damaged neural tissue. The expression of BDNF was increased in various neural cells at the lesion. Additionally, low-energy ESWT increased the area of spared white matter and the number of oligodendrocytes in the injured spinal cord compared with untreated control animals. There were more axonal fibers around the injured site after the application of low-energy ESWT than control. Importantly, low-energy ESWT improved the locomotor functions evaluated by both the BBB scale and ladder rung walking test in addition to the sensory function measured using a von Frey test. Moreover, the electrophysiological assessment confirmed that the conductivity of the central motor pathway in the injured spinal cord was restored by low-energy ESWT. These findings indicate that low-energy ESWT promotes BDNF expression at the lesion site and reduces the neural tissue damage and functional impairment following spinal cord injury. Our results support the potential application of low-energy ESWT as a novel therapeutic strategy for treating spinal cord injury.
•Low-energy extracorporeal shock wave therapy (ESWT) promoted BDNF expression after SCI.•Low-energy ESWT provide neuroprotective effect on the injured spinal cord.•Locomotor and sensory functions following SCI were improved by low-energy ESWT.•Application of low-energy ESWT may be a novel therapeutic strategy for treating SCI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg ...(Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.
These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.
The prevalence of Alzheimer’s disease (AD) has been rapidly increasing worldwide. We have developed a novel angiogenic therapy with low-intensity pulsed ultrasound (LIPUS), which is effective and ...safe in animal models of AD and vascular dementia. We performed two trials of LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety, and a randomized, double-blind, placebo-controlled (RCT) trial for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones for one hour 3 times a week as one session under the special conditions (1.3 MPa, 32 cycles, 5% duty cycle) we identified. The LIPUS therapy was performed for one session in the roll-in trial, and 6 sessions in the RCT trial with 3-month intervals for 1.5 years. The primary endpoint was ADAS-J cog scores. The RCT trial was terminated prematurely due to the COVID-19 pandemic. In the roll-in trial (N = 5), no adverse effects were noted. In the RCT trial (N = 22), the worsening of ADAS-J cog scores tended to be suppressed in the LIPUS group compared with the placebo group at week 72 (P = 0.257). When responders were defined as those with no worsening of ADAS-J cog scores at week 72, the prevalence was 50% (5/10) and 0% (0/5) in the LIPUS and placebo groups, respectively (P = 0.053). No adverse effects were noted. These results suggest that the LIPUS therapy is safe and tends to suppress cognitive impairment although a next pivotal trial with a large number of subjects is warranted.
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