Biomedical subjects

Noritoshi Nagaya

Publications and source records attributed to Noritoshi Nagaya.

At least 19 recordsLinked to original sources

PubMed2007

Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction.

Previous experimental studies have demonstrated that MMPs (matrix metalloproteinases) contribute to LV (left ventricular) remodelling. We hypothesized that cardiac MMPs are activated in patients with AMI (acute myocardial infarction) and, if so, MMP production may be attenuated by statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) through their cardiovascular protective actions. We studied 30 patients, ten control patients with stable angina pectoris and 20 patients with AMI, in whom LV catheterization at the chronic stage was performed 22+/-12 days (value is mean+/-S.D.) after the onset of AMI. Blood samples were collected from the CS (coronary sinus) and a peripheral artery. In patients with AMI, the levels of MMP-2 and MMP-9 were significantly (P<0.05) higher in the CS than the peripheral artery (MMP-2, 853+/-199 compared with 716+/-127 ng/ml; MMP-9, 165+/-129 compared with 98+/-82 ng/ml), whereas no significant differences were observed in the patients with angina pectoris. The CS-arterial concentration gradients of MMP-2 and MMP-9 correlated positively with BNP (brain natriuretic peptide) levels (MMP-2, R=0.68, P<0.01; MMP-9, R=0.59, P<0.05) and LV end-diastolic volume index (MMP-2, R=0.70, P<0.01; MMP-9, R=0.70, P<0.01). When patients with AMI treated with 10 mg of pravastatin or without (n=10 in each group) were compared, this statin therapy significantly (P<0.05) decreased the CS-arterial concentration gradients of MMP-2 (69+/-43 compared with 213+/-185 ng/ml) and MMP-9 (14+/-27 compared with 119+/-84 ng/ml). In conclusion, the enhanced production of cardiac MMP-2 and MMP-9 is associated with LV enlargement and elevated BNP levels in patients with AMI. A pleiotropic effect of statins appears to be associated with the modulation of cardiac MMP activation, which may be potentially beneficial in the attenuation of post-infarction LV remodelling.

Aged↗

PubMed2006

Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans.

BACKGROUND: The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans. METHODS AND RESULTS: Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684+/-549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1+/-0.7 to 1.5+/-1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year. CONCLUSIONS: In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.

Adult↗

PubMed2006

Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis.

Acute myocarditis is a non-ischemic inflammatory disease of the myocardium for which there is currently no specific treatment. We have previously shown that mesenchymal stem cells (MSC) can ameliorate heart injury during acute ischemia and in dilated cardiomyopathy; however, the therapeutic potential in acute myocarditis is unclear. In this study, we investigated the ability of MSC to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Ten-week-old male Lewis rats were injected with porcine myosin to induce myocarditis. Cultured MSC (3x10(6) cells/rat) were injected intravenously 7 days after myosin injection. At 3 weeks, myosin injection resulted in severe inflammation and significant deterioration of cardiac function. MSC transplantation attenuated increases in CD68-positive inflammatory cells and monocyte chemoattractant protein-1 (MCP-1) expression in myocardium, and improved cardiac function in this model. Furthermore, myocardial capillary density was higher in myocarditis tissue, and was further increased by MSC transplantation. In vitro, cultured adult rat cardiomyocytes were injured in response to MCP-1, whereas this effect was attenuated by MSC-derived conditioned medium, suggesting cardioprotective effects of MSC acting in a paracrine manner. MSC transplantation attenuated myocardial injury and dysfunction in a rat model of acute myocarditis, at least in part through paracrine effects of MSC.

Acute Disease↗

PubMed2006

Beraprost sodium enhances neovascularization in ischemic myocardium by mobilizing bone marrow cells in rats.

Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague-Dawley rats, beraprost (200 microg/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administration of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and c-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells.

Animals↗

PubMed2006

Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction.

Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue-derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.

Animals↗

PubMed2006

Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia.

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for GH secretagogue receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. This peptide also stimulates food intake and induces adiposity through GH-independent mechanisms. In addition, ghrelin acts directly on the central nervous system to decrease sympathetic nerve activity. Thus, ghrelin plays important roles for maintaining GH release and energy homeostasis. Repeated administration of ghrelin improves body composition, muscle wasting, functional capacity, and sympathetic augmentation in cachectic patients with heart failure or chronic obstructive pulmonary disease. These results suggest that ghrelin has anti-cachectic effects through GH-dependent and independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of cardiopulmonary-associated cachexia.

Animals↗

PubMed2006

Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1), a pro-inflammatory chemokine, has potent chemoattractant activity for monocytes/macrophages. We sought to investigate the clinical significance of MCP-1 in idiopathic pulmonary arterial hypertension (IPAH). METHODS: This study included 28 patients with IPAH, seven patients with pulmonary arterial hypertension (PAH) related to collagen vascular disease, and 13 healthy subjects. Plasma MCP-1 levels were measured together with serum IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels. RESULTS: Circulating levels of MCP-1, IL-6 and TNF-alpha were significantly higher in patients with IPAH than in healthy controls, although they were lower than in patients with PAH related to collagen vascular disease. Plasma MCP-1 did not significantly correlate with any haemodynamic variables. However, plasma MCP-1 levels correlated negatively with the disease duration (time from symptom onset). CONCLUSIONS: Plasma MCP-1 levels were elevated in patients with IPAH, and this elevation was particularly marked in the early stage of disease. Taking into account the chemoattractant activity of MCP-1, these results imply a contribution of MCP-1 to the development of pulmonary hypertension.

Adolescent↗

PubMed2006

Therapeutic potential of ghrelin in the treatment of heart failure.

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for the GH secretagogues receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated, not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. Considering the haemodynamic and anabolic effects of GH, ghrelin may have beneficial effects on cardiac function and energy metabolism in heart failure through GH-dependent mechanisms. On the other hand, ghrelin has some GH-independent actions: ghrelin stimulates food intake and induces adiposity. Interestingly, ghrelin acts directly on the CNS to decrease sympathetic nerve activity. It also inhibits apoptosis of cardiomyocytes and endothelial cells. An experimental study has shown that repeated administration of ghrelin improves cardiac structure and function, and attenuates the development of cardiac cachexia in chronic heart failure (CHF). These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe CHF.

Animals↗

PubMed2006

Physiological significance and therapeutic potential of adrenomedullin in pulmonary hypertension.

Adrenomedullin (ADM) is a potent vasodilator peptide that was originally isolated from human pheochromocytoma. Its vasodilatory effect is mediated by cyclic adenosine 3',5'-monophosphate- and nitric oxide-dependent mechanisms. Earlier studies have demonstrated that ADM is secreted from various tissues, including vessels, heart, and lungs. In addition, there are specific receptors for ADM in the lungs. Plasma ADM level is elevated in proportion to the severity of pulmonary hypertension, and circulating ADM is partially metabolized in the lungs. These findings suggest that ADM plays an important role in the regulation of pulmonary vascular tone. Administration of ADM by intravenous or intratracheal delivery significantly decreased pulmonary arterial pressure and pulmonary vascular resistance in patients with pulmonary arterial hypertension. Furthermore, we have recently developed a new therapeutic strategy using ADM gene-modified endothelial progenitor cells (EPC). Intravenously administered ADM gene-modified EPC were incorporated into lung tissues and attenuated monocrotaline-induced pulmonary hypertension in rats. In addition, ADM has angiogenic and anti-apoptotic activities via activation of Akt and/or mitogen-activated protein kinase. These findings suggest that ADM may act not only as a vasodilator but also as a vasoprotective factor. Thus, ADM may be a promising endogenous peptide for the treatment of pulmonary hypertension.

Adrenomedullin↗

PubMed2006

Postnatal neovascularization by endothelial progenitor cells immortalized with the simian virus 40T antigen gene.

Endothelial progenitor cells (EPCs) contribute to blood vessel formation in ischemic and tumorous tissues, but comprise only a small population in circulation. We attempted to immortalize putative EPCs from human cord blood. Human CD34+ cord blood cells were cultured in the presence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and transfected with a retroviral vector encoding the simian virus 40 large T (SV40T) antigen. This resulted in the immortalization of cord blood cells, leading to the establishment of several cell lines. One of these lines, HYCEC-1, exhibited a phenotype characteristic of the endothelial lineage, including expression of von Willebrand factor and VEGF receptor-2 (VEGFR-2/KDR/Flk-1) and uptake of acetylated-low density lipoprotein. Flow cytometric analysis revealed that HYCEC-1 cells were strongly positive for CD31 and CD146, moderately positive for CD144, weakly positive for CD133 and CD34, and negative for CD14 and CD45. HYCEC-1 cells formed capillary-like structures on basement matrix gel in vitro. Upon transplantation into the ischemic hind limb of nude rats, HYCEC-1 cells efficiently participated in neovascularization and augmented blood flow. The immortalized HYCEC-1 cells are suggested to be a class of EPCs that can efficiently participate in postnatal neovasculogenesis in the ischemic hind limb, and may also be a useful tool for studying tumor vessel formation.

AC133 Antigen↗

PubMed2006

[Ghrelin].

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Animals↗

PubMed2005

Postexercise VO2 "Hump" phenomenon as an indicator for inducible myocardial ischemia in patients with acute anterior myocardial infarction.

OBJECTIVES: At exercise testing with respiratory gas analysis in patients with inducible myocardial ischemia, we have occasionally observed abnormal transient oxygen uptake (VO2) components with a characteristic "Hump"-shaped morphology early after exercise, which may serve as an index for inducible ischemia. We examined this hypothesis in patients with anterior q-wave myocardial infarction in whom the accuracy to identify ischemia by exercise ECG is limited. DESIGN: From patients with acute anterior q-wave infarction but without clinically overt heart failure who underwent pre-discharge exercise testing, we examined patients with (Group-I, n = 30) and without (Group-N, n = 29) inducible ischemia. To identify "Hump", postexercise VO2 (up to 4 min) standardized for peak VO2 was exponentially fitted with use of peak VO2 and VO2 of 90-240 s, yielding "expected VO2". "D-curve" was obtained by subtracting "expected VO2" from measured VO2. RESULTS: Although exercise-induced ST depressions more frequently appeared in Group-I (27%) than in Group-N (3%, p < 0.05), the prevalence was low. D-curve peaked later (p < 0.01) and its value was greater (p < 0.05) in Group-I than in Group-N. When "Hump" was defined to be present if D-curve peaked > or =40 s and its peak value > or =15%, it was far more frequently found in Group-I (n = 17/30) than in Group-N (n = 1/29, p < 0.01). Thus, "Hump" could diagnose inducible ischemia with a sensitivity of 57% and a specificity of 97%. CONCLUSIONS: Although not highly sensitive, postexercise VO2 "Hump" with its peak occurring around 60 s after exercise is a specific marker for inducible ischemia. The identification may be useful, particularly in patients with limited accuracy of exercise ECG such as those with q-wave anterior infarction.

Exercise Test↗

PubMed2005

A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension.

RATIONALE: The balance between prostacyclin and thromboxane plays an important role in the regulation of pulmonary vascular tone. Recently, we developed ONO-1301, a novel, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. OBJECTIVES: We investigated whether modulation of prostacyclin/thromboxane balance by ONO-1301 ameliorates monocrotaline-induced pulmonary hypertension in rats. METHODS: After subcutaneous injection of monocrotaline or vehicle, rats were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle twice per day for 3 wk. MEASUREMENTS AND MAIN RESULTS: There was significant development of pulmonary hypertension 3 wk after monocrotaline injection. Treatment with ONO-1301 significantly attenuated the increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in monocrotaline rats. Furthermore, ONO-1301 significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in monocrotaline rats. The half-life of plasma ONO-1301 concentration after a single subcutaneous administration was approximately 5.6 h. A single administration of ONO-1301 increased plasma cyclic adenosine 3', 5'-monophosphate level, which lasted at least up to 8 h. Treatment with ONO-1301 significantly decreased plasma 11-dehydro-thromboxane B2, a metabolite of thromboxane, in monocrotaline rats. Finally, Kaplan-Meier survival curves demonstrated that repeated administration of ONO-1301 improved survival rate in monocrotaline rats compared with vehicle administration (80 vs. 30% in 6-wk survival). CONCLUSIONS: Subcutaneous administration of a novel prostacyclin agonist (ONO-1301) markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. The beneficial effects of ONO-1301 may occur through its long-lasting stimulation of cyclic adenosine 3', 5'-monophosphate and inhibition of thromboxane synthase.

Animals↗

PubMed2005

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice.

The balance between prostacyclin and thromboxane A2 (TXA2) plays an important role in pulmonary homeostasis. However, little information is available regarding the therapeutic potency of these prostanoids for pulmonary fibrosis. We have recently developed ONO-1301, a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. Thus we investigated whether repeated administration of ONO-1301 attenuates bleomycin-induced pulmonary fibrosis in mice. After intratracheal injection of bleomycin or saline, mice were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle. Bronchoalveolar lavage (BAL) and histological analyses were performed at 3, 7, and 14 days after bleomycin injection. In vitro studies using mouse lung fibroblasts were also performed. ONO-1301 significantly attenuated the development of bleomycin-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. ONO-1301 significantly reduced total cell count, neutrophil count, and total protein level in BAL fluid in association with a marked reduction of TXB2. A single administration of ONO-1301 significantly increased plasma cAMP level for >2 h. In vitro, ONO-1301 and a cAMP analog dose-dependently reduced cell proliferation in mouse lung fibroblasts. The reduction in cell proliferation by ONO-1301 was attenuated by a protein kinase A (PKA) inhibitor. Furthermore, bleomycin mice treated with ONO-1301 had a significantly higher survival rate than those given vehicle. These results suggest that repeated administration of ONO-1301 attenuates the development of bleomycin-induced pulmonary fibrosis and improves survival in bleomycin mice, at least in part by inhibition of TXA2 synthesis and activation of the cAMP/PKA pathway.

Animals↗

PubMed2005

Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy.

BACKGROUND: Pluripotent mesenchymal stem cells (MSCs) differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells. However, little information is available about the therapeutic potency of MSC transplantation in cases of dilated cardiomyopathy (DCM), an important cause of heart failure. METHODS AND RESULTS: We investigated whether transplanted MSCs induce myogenesis and angiogenesis and improve cardiac function in a rat model of DCM. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. Cultured MSCs secreted large amounts of the angiogenic, antiapoptotic, and mitogenic factors vascular endothelial growth factor, hepatocyte growth factor, adrenomedullin, and insulin-like growth factor-1. Five weeks after immunization, MSCs or vehicle was injected into the myocardium. Some engrafted MSCs were positive for the cardiac markers desmin, cardiac troponin T, and connexin-43, whereas others formed vascular structures and were positive for von Willebrand factor or smooth muscle actin. Compared with vehicle injection, MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium, resulting in decreased left ventricular end-diastolic pressure (11+/-1 versus 16+/-1 mm Hg, P<0.05) and increased left ventricular maximum dP/dt (6767+/-323 versus 5138+/-280 mm Hg/s, P<0.05). CONCLUSIONS: MSC transplantation improved cardiac function in a rat model of DCM, possibly through induction of myogenesis and angiogenesis, as well as by inhibition of myocardial fibrosis. The beneficial effects of MSCs might be mediated not only by their differentiation into cardiomyocytes and vascular cells but also by their ability to supply large amounts of angiogenic, antiapoptotic, and mitogenic factors.

Animals↗

PubMed2005

Altered expression balance of matrix metalloproteinases and their inhibitors in human carotid plaque disruption: results of quantitative tissue analysis using real-time RT-PCR method.

BACKGROUND: The balance between degradation and synthesis of extracellular matrix determines its content in atherosclerotic tissue. To examine the role of expression balance of matrix metalloproteinases (MMPs) to their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) and tissue factor pathway inhibitor-2 (TFPI-2) in the development and disruption of atherosclerotic plaque, these gene expressions in human carotid plaque were quantitatively determined by real-time reverse transcription (RT)-polymerase chain reaction (PCR) method. METHODS: Total RNA for cDNA synthesis was extracted from tissues in 24 patients with carotid endarterectomy. The amounts of cDNAs for MMP-1, -2, -3 and -9, TFPI-2 and TIMP-1, -2 and -3 were determined by real-time RT-PCR method, and normalized with glutaraldehyde 3-dehydrogenase. RESULTS: In plaques, the expression MMP-1 (1.53+/-0.25, mean+/-S.E.M.), MMP-3 (1.99+/-0.59) and MMP-9 (2.00+/-0.51) was augmented compared to those in the adjacent control regions (0.60+/-0.16, 0.46+/-0.18 and 0.58+/-0.21, respectively, p<0.05). The expression of TFPI-2 was lower in plaques (0.32+/-0.08) than in controls (0.94+/-0.23, p<0.01). Although the expression of TIMP-1 was higher in plaques (1.28+/-0.23) than in controls (0.81+/-0.10, p<0.05), the indices of MMP-1/TIMP-1, MMP-3/TIMP-3 and MMP-9/TIMP-1 were still significantly higher in plaques. Interestingly, MMP-9 and the resulting MMP-9/TIMP-1 balance in plaques with disruption were significantly higher (3.36+/-1.52 and 1.66+/-0.12, n=11) than those in non-disrupted plaques (1.11+/-0.52 and 0.76+/-0.12, n=13, p<0.05). CONCLUSION: With the decreased expression of TFPI-2, upregulation of MMPs in atherosclerotic plaque was disproportional to that of TIMPs, suggesting that imbalanced degradation and synthesis of extracellular matrix persists in advanced lesions, particularly in plaques with disruption.

Aged↗

PubMed2005

Adrenomedullin regenerates alveoli and vasculature in elastase-induced pulmonary emphysema in mice.

RATIONALE: Adrenomedullin, a potent vasodilator peptide, regulates cell growth and survival. However, whether adrenomedullin contributes to lung regeneration remains unknown. OBJECTIVES: To investigate whether adrenomedullin influences the kinetics of bone marrow cells, and whether adrenomedullin promotes regeneration of alveoli and vasculature and thereby improves lung structure and function in elastase-induced emphysema in mice. METHODS: Adrenomedullin or vehicle was randomly administered to C57BL/6 mice for 5 days. We counted the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. After intratracheal injection of elastase or saline, mice were randomized to receive continuous infusion of adrenomedullin or vehicle for 14 days. Functional and histologic analyses were performed 28 days after treatment. RESULTS: Twenty-eight days after elastase injection, destruction of the alveolar walls was observed. However, adrenomedullin infusion significantly inhibited the increase in lung volume, static lung compliance, and mean linear intercept in mice given elastase. Adrenomedullin increased the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. Adrenomedullin significantly increased the number of bone marrow-derived cells incorporated into the elastase-treated lung. Some of these cells were positive for cytokeratin or von Willebrand factor. Infusion of adrenomedullin after the establishment of emphysema also had beneficial effects on lung structure and function. In vitro, addition of adrenomedullin attenuates elastase-induced cell death in alveolar epithelial cells and endothelial cells. CONCLUSIONS: Adrenomedullin improved elastase-induced emphysema at least in part through mobilization of bone marrow cells and the direct protective effects on alveolar epithelial cells and endothelial cells.

Adrenomedullin↗

PubMed2005

Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats.

BACKGROUND AND PURPOSE: Adrenomedullin (AM) induces angiogenesis and inhibits cell apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. Transplantation of mesenchymal stem cells (MSCs) has been shown to improve neurological deficits after stroke in rats. We investigated whether AM enhances the therapeutic potency of MSC transplantation. METHODS: Male Lewis rats (n=100) were subjected to 2-hour middle cerebral artery occlusion. Immediately after reperfusion, rats were assigned randomly to receive intravenous transplantation of MSCs plus subcutaneous infusion of AM for 7 days (MSC+AM group), AM infusion alone (AM group), MSC transplantation alone (MSC group), or vehicle infusion (control group). Neurological and immunohistological assessments were performed to examine the effects of these treatments. RESULTS: Some engrafted MSCs were positive for neuronal and endothelial cell markers, although the number of differentiated MSCs did not differ significantly between the MSC and MSC+AM groups. The neurological score significantly improved in the MSC, AM, and MSC+AM groups compared with the control group. Importantly, improvement in the MSC+AM group was significantly greater than that in the MSC and AM groups. There was marked induction of angiogenesis in the ischemic penumbra in the MSC+AM group, followed by the AM, MSC, and control groups. AM infusion significantly inhibited apoptosis of transplanted MSCs. As a result, the number of engrafted MSCs in the MSC+AM group was significantly higher than that in the MSC group. CONCLUSIONS: AM enhanced the therapeutic potency of MSCs, including neurological improvement, possibly through inhibition of MSC apoptosis and induction of angiogenesis.

Adrenomedullin↗