Yuuki Shimizu - Academia.edu (original) (raw)
Papers by Yuuki Shimizu
International Journal of Molecular Sciences
Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following ... more Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational ...
Angiogenesis
Background Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputa... more Background Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. Objectives We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. Methods The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. Results The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm 2 at to 109 mm 2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. Conclusions Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015. Keywords Adipose-derived regenerative cells • Therapeutic angiogenesis • Critical limb ischemia • Multicenter clinical trial Abbreviations ABI Ankle-brachial pressure index ADRC Adipose-derived regenerative cell ASO Arterio-sclerosis obliterans CLI Critical limb ischemia CTD Connective tissue disease NRS Numerical rating scale SPP Skin perfusion pressure TAO Thromboangiitis obliterans QOL Quality of life
Cardiovascular Research, 2021
Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity cont... more Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. Methods and results apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflamm...
Journal of molecular and cellular cardiology, Aug 21, 2016
Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed t... more Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following myocardial ischemia-reperfusion (I/R) injury. In response to I/R injury, DJ-1 KO mice displayed increased areas of infarction and worsened left ventricular function when compared to WT mice, confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process that regulates various aspects of protein function. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins and reduced SUMO-2/3 modified proteins. Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP1 was reduced, whereas the expression of SENP5 was enhanced in DJ-1 KO hearts after I/R injury. Fin...
Journal of Cardiology Cases, 2010
Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a cli... more Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a clinical problem. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high resolution intravascular imaging modality, and is able to distinguish several components of intracoronary structures. In vivo images of in-stent restenosis (ISR) lesions in an SVG using OCT have not been reported. In this case report, we present the characteristics of in vivo OCT images from an ISR lesion of an SVG after BMS implantation.
Internal Medicine, 2013
A 75-year-old Japanese woman with acute mitral valve prolapse and regurgitation, that developed o... more A 75-year-old Japanese woman with acute mitral valve prolapse and regurgitation, that developed one month previously, suffered from intractably progressive congestive heart failure (CHF). However, the emergent surgery was declined, and pharmacological treatment was discontinued due to hypotension and malignant arrhythmia. She was treated with 5-8 cmH2O of continuous positive airway pressure (CPAP) to manage CHF and Cheyne-Stokes respiration during the preoperative period of five weeks, after which plastic surgery of the mitral valve was successfully performed. CPAP can be an effective non-pharmacological treatment for CHF, unloading the left ventricle hydrostatically in order to reduce mitral regurgitation and improve oxygenation.
Journal of the American Heart Association, Jan 19, 2013
Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adip... more Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down-regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms. A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin-knockout mice showed the greater diameter of the injured tail compared with wild-type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild-type and adiponectin-knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP-...
Journal of the American Heart Association, 2021
Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health... more Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model ( P <0.05). The jet‐lag condition deteriorated tissue capillary formation ( P <0.001) and tissue blood perfusion recovery ( P <0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock ...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2021
Objective: Lymphatic vessels are distributed throughout the body and tightly collaborate with blo... more Objective: Lymphatic vessels are distributed throughout the body and tightly collaborate with blood vessels to maintain tissue homeostasis. However, the functional roles of lymphangiogenesis in the process of reparative angiogenesis in ischemic tissues are largely unknown. Accordingly, we investigated potential roles of lymphangiogenesis using a mouse model of ischemia-induced angiogenesis. Approach and Results: Male C57BL/6J mice were subjected to unilateral hindlimb ischemia, in which not only angiogenesis but also lymphangiogenesis was induced. Next, the excessive and prolonged tissue edema model significantly deteriorated reparative angiogenesis and blood perfusion recovery in ischemic limbs. Finally, implantation of adipose-derived regenerative cells augmented ischemia-induced lymphangiogenesis, which was accompanied by reduced tissue edema and inflammation, resulting in improving reparative angiogenesis and blood perfusion recovery. In addition, inhibition of lymphangiogenesis...
Nagoya Journal of Medical Science, 2021
Adipose-derived regenerative cells (ADRCs), mesenchymal stem/progenitor cells from subcutaneous a... more Adipose-derived regenerative cells (ADRCs), mesenchymal stem/progenitor cells from subcutaneous adipose tissue, have been shown to stimulate angiogenesis in hind limb ischemia, an effect attributed to paracrine action on endothelial cells (ECs) in mice. Despite promising therapeutic effects, the relevant molecules promoting neovascularization in this setting have not been fully elucidated. Extracellular vesicles, crucial mediators of intercellular communication, are recognized as a new therapeutic modality for regenerative medicine. Here, we found that GW4869, an exosome biogenesis inhibitor targeting neutral sphingomyelinase, impaired ADRCs-mediated angiogenesis and improvement of blood perfusion in a murine hind limb ischemia model. In addition, while the supernatant of ADRCs induced murine EC migration, this effect was attenuated by pre-treatment with GW4869. RNA analysis revealed that treatment of ADRCs with GW4869 reduced the expression of microRNA-21 (miR-21), miR-27b, miR-322...
Circulation Reports, 2020
their quality of life (QOL) and increases deaths from cardiovascular complications. 1,3 Although ... more their quality of life (QOL) and increases deaths from cardiovascular complications. 1,3 Although endovascular angioplasty or bypass surgery for these patients is recommended by guidelines, 1,4 we still have no effective optimal management strategies for patients with more severe disease, such as long calcification lesions below the knee in B ecause approximately 202 million people are affected by lower extremity arterial disease worldwide, advanced cases of patients with critical limb ischemia (CLI) are a serious health problem, especially in developing countries. 1,2 Major lower extremity amputation surgery is often required for these patients, which significantly reduces
Journal of Biological Chemistry, 2019
Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercel... more Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo. To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.
Journal of the American Heart Association, 2018
Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aid... more Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Methods and Results Mice (C57 BL /6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ...
Journal of molecular and cellular cardiology, Jan 29, 2018
Hydrogen sulfide (HS) is an important regulator of mitochondrial bioenergetics, but its role in r... more Hydrogen sulfide (HS) is an important regulator of mitochondrial bioenergetics, but its role in regulating mitochondrial biogenesis is not well understood. Using both genetic and pharmacological approaches, we sought to determine if HS levels directly influenced cardiac mitochondrial content. Mice deficient in the HS-producing enzyme, cystathionine γ-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild-type hearts. In contrast, mice overexpressing CSE (CSE Tg) and mice supplemented with the orally active HS-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac HS levels influenced the nuclear localization and transcriptional activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) with higher levels having a positive influence and lower levels having a negative influence. Studies aimed at evaluating the underlying mechanisms found that HS required AMP-activated...
American journal of physiology. Heart and circulatory physiology, 2016
Circulation journal : official journal of the Japanese Circulation Society, Jan 25, 2017
Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular diseas... more Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.Methods and Results:Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not im...
Circulation. Heart failure, 2016
Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective eff... more Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear factor E2-related factor 2 (Nrf2) is a cellular target of H2S and facilitator of H2S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure. Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type littermates were subjected to ischemic-induced heart failure. Wild-type mice treated with H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at eval...
Circulation journal : official journal of the Japanese Circulation Society, Jan 25, 2015
International Journal of Molecular Sciences
Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following ... more Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational ...
Angiogenesis
Background Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputa... more Background Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. Objectives We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. Methods The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. Results The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm 2 at to 109 mm 2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. Conclusions Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015. Keywords Adipose-derived regenerative cells • Therapeutic angiogenesis • Critical limb ischemia • Multicenter clinical trial Abbreviations ABI Ankle-brachial pressure index ADRC Adipose-derived regenerative cell ASO Arterio-sclerosis obliterans CLI Critical limb ischemia CTD Connective tissue disease NRS Numerical rating scale SPP Skin perfusion pressure TAO Thromboangiitis obliterans QOL Quality of life
Cardiovascular Research, 2021
Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity cont... more Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. Methods and results apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflamm...
Journal of molecular and cellular cardiology, Aug 21, 2016
Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed t... more Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following myocardial ischemia-reperfusion (I/R) injury. In response to I/R injury, DJ-1 KO mice displayed increased areas of infarction and worsened left ventricular function when compared to WT mice, confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process that regulates various aspects of protein function. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins and reduced SUMO-2/3 modified proteins. Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP1 was reduced, whereas the expression of SENP5 was enhanced in DJ-1 KO hearts after I/R injury. Fin...
Journal of Cardiology Cases, 2010
Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a cli... more Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a clinical problem. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high resolution intravascular imaging modality, and is able to distinguish several components of intracoronary structures. In vivo images of in-stent restenosis (ISR) lesions in an SVG using OCT have not been reported. In this case report, we present the characteristics of in vivo OCT images from an ISR lesion of an SVG after BMS implantation.
Internal Medicine, 2013
A 75-year-old Japanese woman with acute mitral valve prolapse and regurgitation, that developed o... more A 75-year-old Japanese woman with acute mitral valve prolapse and regurgitation, that developed one month previously, suffered from intractably progressive congestive heart failure (CHF). However, the emergent surgery was declined, and pharmacological treatment was discontinued due to hypotension and malignant arrhythmia. She was treated with 5-8 cmH2O of continuous positive airway pressure (CPAP) to manage CHF and Cheyne-Stokes respiration during the preoperative period of five weeks, after which plastic surgery of the mitral valve was successfully performed. CPAP can be an effective non-pharmacological treatment for CHF, unloading the left ventricle hydrostatically in order to reduce mitral regurgitation and improve oxygenation.
Journal of the American Heart Association, Jan 19, 2013
Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adip... more Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down-regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms. A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin-knockout mice showed the greater diameter of the injured tail compared with wild-type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild-type and adiponectin-knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP-...
Journal of the American Heart Association, 2021
Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health... more Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model ( P <0.05). The jet‐lag condition deteriorated tissue capillary formation ( P <0.001) and tissue blood perfusion recovery ( P <0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock ...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2021
Objective: Lymphatic vessels are distributed throughout the body and tightly collaborate with blo... more Objective: Lymphatic vessels are distributed throughout the body and tightly collaborate with blood vessels to maintain tissue homeostasis. However, the functional roles of lymphangiogenesis in the process of reparative angiogenesis in ischemic tissues are largely unknown. Accordingly, we investigated potential roles of lymphangiogenesis using a mouse model of ischemia-induced angiogenesis. Approach and Results: Male C57BL/6J mice were subjected to unilateral hindlimb ischemia, in which not only angiogenesis but also lymphangiogenesis was induced. Next, the excessive and prolonged tissue edema model significantly deteriorated reparative angiogenesis and blood perfusion recovery in ischemic limbs. Finally, implantation of adipose-derived regenerative cells augmented ischemia-induced lymphangiogenesis, which was accompanied by reduced tissue edema and inflammation, resulting in improving reparative angiogenesis and blood perfusion recovery. In addition, inhibition of lymphangiogenesis...
Nagoya Journal of Medical Science, 2021
Adipose-derived regenerative cells (ADRCs), mesenchymal stem/progenitor cells from subcutaneous a... more Adipose-derived regenerative cells (ADRCs), mesenchymal stem/progenitor cells from subcutaneous adipose tissue, have been shown to stimulate angiogenesis in hind limb ischemia, an effect attributed to paracrine action on endothelial cells (ECs) in mice. Despite promising therapeutic effects, the relevant molecules promoting neovascularization in this setting have not been fully elucidated. Extracellular vesicles, crucial mediators of intercellular communication, are recognized as a new therapeutic modality for regenerative medicine. Here, we found that GW4869, an exosome biogenesis inhibitor targeting neutral sphingomyelinase, impaired ADRCs-mediated angiogenesis and improvement of blood perfusion in a murine hind limb ischemia model. In addition, while the supernatant of ADRCs induced murine EC migration, this effect was attenuated by pre-treatment with GW4869. RNA analysis revealed that treatment of ADRCs with GW4869 reduced the expression of microRNA-21 (miR-21), miR-27b, miR-322...
Circulation Reports, 2020
their quality of life (QOL) and increases deaths from cardiovascular complications. 1,3 Although ... more their quality of life (QOL) and increases deaths from cardiovascular complications. 1,3 Although endovascular angioplasty or bypass surgery for these patients is recommended by guidelines, 1,4 we still have no effective optimal management strategies for patients with more severe disease, such as long calcification lesions below the knee in B ecause approximately 202 million people are affected by lower extremity arterial disease worldwide, advanced cases of patients with critical limb ischemia (CLI) are a serious health problem, especially in developing countries. 1,2 Major lower extremity amputation surgery is often required for these patients, which significantly reduces
Journal of Biological Chemistry, 2019
Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercel... more Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo. To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.
Journal of the American Heart Association, 2018
Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aid... more Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Methods and Results Mice (C57 BL /6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ...
Journal of molecular and cellular cardiology, Jan 29, 2018
Hydrogen sulfide (HS) is an important regulator of mitochondrial bioenergetics, but its role in r... more Hydrogen sulfide (HS) is an important regulator of mitochondrial bioenergetics, but its role in regulating mitochondrial biogenesis is not well understood. Using both genetic and pharmacological approaches, we sought to determine if HS levels directly influenced cardiac mitochondrial content. Mice deficient in the HS-producing enzyme, cystathionine γ-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild-type hearts. In contrast, mice overexpressing CSE (CSE Tg) and mice supplemented with the orally active HS-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac HS levels influenced the nuclear localization and transcriptional activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) with higher levels having a positive influence and lower levels having a negative influence. Studies aimed at evaluating the underlying mechanisms found that HS required AMP-activated...
American journal of physiology. Heart and circulatory physiology, 2016
Circulation journal : official journal of the Japanese Circulation Society, Jan 25, 2017
Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular diseas... more Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.Methods and Results:Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not im...
Circulation. Heart failure, 2016
Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective eff... more Therapeutic strategies aimed at increasing hydrogen sulfide (H2S) levels exert cytoprotective effects in various models of cardiovascular injury. However, the underlying mechanism(s) responsible for this protection remain to be fully elucidated. Nuclear factor E2-related factor 2 (Nrf2) is a cellular target of H2S and facilitator of H2S-mediated cardioprotection after acute myocardial infarction. Here, we tested the hypothesis that Nrf2 mediates the cardioprotective effects of H2S therapy in the setting of heart failure. Mice (12 weeks of age) deficient in Nrf2 (Nrf2 KO; C57BL/6J background) and wild-type littermates were subjected to ischemic-induced heart failure. Wild-type mice treated with H2S in the form of sodium sulfide (Na2S) displayed enhanced Nrf2 signaling, improved left ventricular function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2S therapy failed to provide protection against heart failure in Nrf2 KO mice. Studies aimed at eval...
Circulation journal : official journal of the Japanese Circulation Society, Jan 25, 2015