Biomedical subjects
Publications and source records attributed to H Hosokawa.
Intravascular ultrasound analysis of 70 chronic total occlusions (CTOs), conducted either before intervention or following dilation of a 1.5-mm balloon, showed that older CTOs have more complex plaque composition including a larger calcific burden. This may explain the adverse revascularization profile of older CTOs.
Transforming growth factor-beta1 (TGF-beta1) is an inhibitory cytokine increasingly recognized as a key factor for immuno-regulation. The function of IL-4 in the regulation of TGF-beta1 production from T cells has been reported previously; however, the precise molecular mechanism still remains to be elucidated. For a better understanding of the mechanism involved in regulation, we have investigated a relationship between the STAT6-dependent pathway and TGF-beta1 production from naïve T cells. TCR crosslinking initiates TGF-beta1 production in CD4(+) T cells, and IL-4-mediated signaling enhances the TGF-beta1 production from naïve CD4(+) T cells. The IL-4-mediated up-regulation of TGF-beta1 production from naïve CD4(+) T cells is elicited in STAT6-deficient (STAT6 KO) mice, but not in IL-4 receptor-deficient (IL-4R KO) mice. These results clearly demonstrate that a STAT6-independent pathway is working in IL-4-mediated enhancement of TGF-beta1 production from naïve CD4(+) T cells. Moreover, the addition of IL-4 showed no additive effect on TGF-beta1 promoter-mediated transcription stimulated by TCR. Therefore, we hypothesize that the IL-4-mediated signaling does not work directly on the transcription of the TGF-beta1 gene, but rather regulates the expansion of TGF-beta1-secreting T cells.
This case report describes a new technique for repairing pararenal aortic aneurysms with a transluminally placed triple-branched stent graft with sidearms extending into the superior mesenteric artery and renal arteries. Endovascular repair with the branched stent graft was attempted in two patients with a pararenal aortic Aneurysm. Stent grafting was technically successful in both patients. Although postoperative transient renal function impairment and paralytic ileus occurred in patient 2, these complications were gradually resolved in the perioperative period. A substantial shrinkage of the aneurysm was revealed by means of computed tomographic measurements in patient 1. In both patients, complete exclusion of the aneurysm and patency of the bilateral renal arteries and the superior mesenteric artery were confirmed by means of follow-up computed tomographic images at 2 years. This minimally invasive approach for pararenal aortic aneurysms appears to be a viable therapeutic option for patients who are at high risk for open surgery.
Bullous pemphigoid (BP) is an autoimmune disease frequently occurring in elderly persons. It has been reported that 92-kDa gelatinase released from eosinophils cleaves the extracellular domain of BP180 protein, suggesting a direct role of eosinophils in bulla formation in this disease. The expression of the high-affinity IgE receptor, Fc epsilon RI, on eosinophils was examined in patient with BP. Samples of affected skin obtained from 7 patients with BP were stained immunohistochemically by the alkaline phosphatase anti-alkaline phosphatase (APAAP) method and mirror sections were examined. Eosinophils were present at a rate of 1.0-19.0% in lesions of the dermis, and the number of IgE-positive cells exceeded that of Fc epsilon RI-positive cells in all cases. These cells were not detected in the epidermis, and examination of mirror sections confirmed that the Fc epsilon RI-positive cells corresponded to eosinophils. It has been demonstrated that Fc epsilon RI-positive cells are involved in the dermal lesions of BP. The activation of eosinophils by Fc epsilon RI may participate in the pathogenesis of BP by triggering the degranulation of mast cells.
Vascular hypertrophy occurs during chronic hypertension and contributes to the elevation of peripheral vascular resistance in hypertension. In this study, we examined whether acute pressure overloading of the vascular wall produces activation of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in isolated perfused rat aortae, and examined whether the mechanical overloading-induced MAP kinase activation is mediated via the vascular angiotensin system. Aortae were perfused with Tyrode solution. Increases in perfusion pressure caused a pressure-dependent increase in MAP kinase activity in endothelium-intact aortae and in endothelium-denuded aortae. The increase in MAP kinase activity induced by pressure loading was inhibited by the angiotensin receptor antagonist, losartan, the renin inhibitor, pepstatin A, and the angiotensin-converting enzyme inhibitor, captopril. Ca(2+) depletion and the Ca(2+) channel antagonist, nifedipine, did not affect the pressure loading-induced MAP kinase activation. The results of the present study suggest that pressure loading of the vascular wall per se can activate MAP kinases in the vasculature and that the MAP kinase activation is mediated at least partly via the vascular angiotensin system. It seems unlikely that the pressure loading-induced increase in MAP kinase activity is mainly mediated via increases in Ca(2+) influx in vascular cells.
OBJECTIVES: We sought to determine whether left ventricular (LV) postsystolic shortening in the region of acute myocardial infarction (MI) predicts functional recovery after primary angioplasty. BACKGROUND: Previous studies in experimental animals have shown that postsystolic shortening during temporary coronary occlusion predicts functional recovery after reperfusion. METHODS: Contrast ventriculography was performed on 35 patients with acute MI before and immediately after angioplasty, and one day, one month, three months and one year later. The centerline method was used to measure regional LV wall motion at end systole from all six ventriculograms as well as motion during isovolumic relaxation (motion(iso)) and postsystolic shortening from end systole until the end of contraction. The ventriculograms of 23 patients with normal anatomy were similarly analyzed. RESULTS: Wall motion at end systole improved significantly from baseline to follow-up in the infarct region. Postsystolic shortening at baseline correlated most closely with the recovery of wall motion at three months in patients with anterior infarction (r = 0.69, n = 25, p = 0.0001) but also with recovery at one month and one year. The correlation was slightly less powerful for motion(iso). Functional recovery could not be predicted from assessment of motion(iso) and postsystolic shortening in patients with inferior infarction. CONCLUSIONS: In patients with acute anterior MI, analysis of postsystolic shortening in the infarct region predicts the recovery of systolic LV function after reperfusion. Postsystolic shortening represents active contraction and indicates viable myocardium.
Recognition and uptake of apoptotic cells by neighboring phagocytes is essential for the clearance of dying cells without accompanying inflammation or tissue damage. In the thymus, many apoptotic cells are generated in the process of negative selection, and both thymic macrophages (professional phagocytes) and nursing thymic epithelial cells (nursing TEC; nonprofessional phagocytes) recognize and ingest them. However the receptors responsible for this recognition and uptake have not been identified. In the present study, we have established a human nursing TEC line and examined the expression of several genes of the scavenger receptor family considered to be potential receptors for apoptotic cells. Human scavenger receptor-B1 (hSR-B1)/CLA-1, previously shown to recognize apoptotic cells, was strongly expressed in nursing TEC, whereas there was little or no expression of the other scavenger receptors tested: scavenger receptor class A, CD36, or CD68. Suppression of hSR-B1/CLA-1 expression using antisense oligonucleotides decreased the binding of apoptotic thymocytes to nursing TEC by more than 40%. These results indicate that hSR-B1/CLA-1 may play a major role in the clearance of apoptotic cells in the thymus, mediating the recognition and ingestion of apoptotic thymocytes by nursing TEC.
Although transforming growth factor-beta (TGF-beta) stimulates pancreatic islet cells to synthesize and secret insulin, the mechanism underlying this effect is not known. To investigate this question, we examined the insulin promoter activity focusing on a transcription factor, pancreatic and duodenal homeobox gene-1 (PDX-1) that binds to the A3 element of the rat insulin promoter. Studies performed using the rat insulinoma cell line, INS-1 showed that TGF-beta stimulation of endogenous insulin mRNA expression correlated with increased activity of a reporter construct containing the insulin promoter. A potential mechanism for this increase arose from, electrophoretic mobility shift assay showing that the nuclear extract from TGF-beta treated cells contained higher levels of A3 binding activity. Western blot analysis confirmed that PDX-1 was increased in the nuclear extract from INS-1 cells treated with TGF-beta. As expected, a mutant insulin promoter that lacked the PDX-1 binding site was not stimulated by TGF-beta. In summary, the results of these studies show that TGF-beta stimulates the transcription of insulin gene and this action is mediated by the transcription factor, PDX-1.
BACKGROUND: Recently, thoracic aortic stent grafting has emerged as an alternative therapeutic modality for patients with thoracic aortic aneurysms and aortic dissections. However, its application has been limited to descending thoracic aortic aneurysms distal to the aortic arch. We report our initial clinical experience of endovascular branched stent graft repair for aortic arch aneurysms. METHODS AND RESULTS: Endovascular grafting with Inoue branched stent grafts was attempted for 15 patients with thoracic aortic aneurysms and aortic dissections under local anesthesia (n=14) or general anesthesia (n=1). Single-branched stent grafts were used in 14 patients, and a triple-branched stent graft in one. The branched stent grafts were delivered through a 22F or a 24F sheath under fluoroscopic guidance and implanted across the aneurysmal aortic arch. In 2 patients, the single-branched stent graft did not pass through the 22F sheath used. Complete thrombosis of the aneurysm was ultimately achieved in 11 patients (73%). Of 4 persistent leaks, 1 minor leak spontaneously thrombosed and 1 major leak was successfully treated by additional straight stent graft placement. In 1 patient, the right external iliac artery ruptured during the withdrawal of the sheath and was successfully repaired by the implantation of a straight stent graft. One patient with severe stenosis of the aortic graft section was successfully managed by additional stent deployment. Peripheral microembolization to a toe occurred in 1 patient, and cerebral infarction occurred in 1 other patient. Two patients who had failed to receive endovascular stent grafts died during an average follow-up of 12.6 months, 1 of pneumonia and the other of rupture of a concomitant abdominal aortic aneurysm. CONCLUSIONS: This report demonstrates the technical feasibility of endovascular branched stent graft repair for aneurysms located at the aortic arch. Careful, longer follow-up and further extensive clinical trials are awaited toward establishing this technique as a recommendable alternative to surgical treatment of thoracic aortic aneurysms.
Although Gas6 is identified as a growth factor for vascular smooth muscle cells (VSMCs), its roles in these cells have not been clearly elucidated. To examine the role of Gas6 in atherosclerosis, we examined the effects of Gas6 on scavenger receptor family expression in VSMCs. Scavenger receptor class A, one of the scavenger receptor family members, was upregulated in VSMCs by Gas6. Furthermore, the atherogenic lipoprotein, oxidized LDL, induced Gas6 production in these cells. These results indicate that Gas6 plays an important role in foam cell formation in human VSMCs.
BACKGROUND: The process of progression in coronary artery disease is unknown. METHODS AND RESULTS: The subjects were 36 patients with 36 objective vessels with clinically significant progression of coronary artery disease (>/=15% per year) in whom 4 serial coronary arteriograms (CAGs) were performed at intervals of approximately 4 months in a 1-year period. The degree of progression of percent stenosis between each of 2 serial CAGs was classified as marked (M: >/=15%), slight (S: 5% to 14%), and no progression (N: <5%). From the pattern of progression, the 36 vessels were classified as 14 type 1 vessels with marked progression (N-->N-->M in 13 vessels and S-->S-->M in 1 vessel) and 22 type 2 vessels without marked progression (S-->S-->S in 18 vessels, N-->S-->S in 4). Percent stenosis at the first, second, third, and final CAGs was 44+/-14%, 46+/-13%, 46+/-13%, and 88+/-10% (P<0.05 versus first CAG) in type 1 vessels and 44+/-11%, 50+/-9%, 59+/-9%, and 67+/-9% in type 2 vessels (P<0.05 for second, third, and final CAGs versus first CAG). Type 1 vessels featured the sudden appearance of severe stenosis due to marked progression, angina pectoris, or myocardial infarction (71%) and Ambrose type II eccentric lesions indicating plaque rupture or thrombi (57%). Type 2 vessels featured continuous slight progression of stenosis with smooth vessel walls; angina pectoris (14%) occurred when the percent stenosis reached a severe level. An increase in serum C-reactive protein was observed only in the type 2 vessel group, which suggests a relation between continuous slight progression and inflammatory change. CONCLUSIONS: Two types of stenosis progression provide a new insight into the mechanism of coronary artery disease.
CAT3 (cationic amino acid transporter 3) is a member of the murine CAT family which bears a system y(+) transport activity. On the Northern blot of adult rat tissues, the expression of CAT3 is restricted to the brain. In the present study, cellular localization of CAT3 mRNA and protein in the adult rat brain sections was examined by in situ hybridization with cRNA and immunostaining with a CAT3-specific antiserum, respectively. CAT3 mRNA was present both in the cerebral and cerebellar gray matter but most prominently in the nuclei located in the ventromedial part of the brain. These included preoptic nucleus, hypothalamic nucleus, reticular nucleus of thalamus, substantia nigra, central gray around the third ventricle and amygdala. CAT3 protein was also detected both in the cerebral and cerebellar gray matter and strong immunostaining was obtained in the olfactory cortex, hippocampus and cerebellar granular and Purkinje cell layers. Observations at higher magnifications revealed that both mRNA and protein were expressed by neurons but neither by glial nor endothelial cells. These results confirm the neuron-specificity of CAT3 in the adult rat brain and indicate that CAT3 is responsible for the neuronal system y(+) activity. The discrepancy between the distribution of mRNA and its translation product suggests a regional difference in the translation rate of the CAT3 transcript.
The present study shows that acute myocardial infarction affects the left ventricle at the base as well as in the infarct region by widening of the angle between the mitral and aortic valve planes. The valve plane angle did not change over time despite significant recovery of left ventricular function, suggesting that acute myocardial infarction causes irreversible structural changes in the left ventricular myocardium remote from the infarct region.
The chemokine monocyte chemoattractant protein-1 is a potent chemoattractant for monocytes. Monocyte chemoattractant protein-1 is produced by vascular endothelial cells during inflammatory diseases such as atherosclerosis. In this study, we examined the effects of a thiazolidinedione on monocyte chemoattractant protein-1 expression in human vascular endothelial cells. In human vascular endothelial cells, interleukin-1beta and tumor necrosis factor-alpha induced endogenous monocyte chemoattractant protein-1 protein secretion, mRNA expression and promoter activity. The thiazolidinedione inhibited these effects. In summary, our results indicated that the suppression of the expression of monocyte chemoattractant protein-1 can be accomplished by thiazolidinedione treatment, raising the possibility that thiazolidinedione may be of therapeutic value in the treatment of diseases such as atherosclerosis.
The chemokine RANTES is a potent chemoattractant for eosinophils. RANTES is produced by lung epithelial cells during eosinophil-rich inflammatory diseases such as asthma. In this study, we examined the effects of thiazolidinediones (TZD) on RANTES expression in a human lung epithelial cell line, A549. In A549 cells, interleukin-1beta and tumor necrosis factor-alpha induced endogenous RANTES protein secretion, mRNA expression, and promoter activity. The TZD inhibited these effects. Our data indicate that the suppression of the expression of RANTES can be accomplished by TZD treatment, raising the possibility that TZD might be of therapeutic value in diseases such as asthma.
Expression of dystroglycan (DG) by cultured bovine aortic endothelial (BAE) cells was confirmed by cDNA cloning from a BAE cDNA library, Northern blotting of mRNA, Western blotting of membrane proteins, and double immunostaining with antibodies against betaDG and platelet endothelial cell adhesion molecule-1. Immunocytochemical analysis revealed localization of DG in multiple plaques on the basal side of resting cells. This patchy distribution was obscured in migrating cells, in which the most prominent staining was observed in the trailing edge anchoring the cells to the substratum. Biotin-labeled laminin-1 overlay assay of dissociated BAE membrane proteins indicated the interaction of laminin-1 with alphaDG. The laminin alpha5 globular domain fragment expressed in bacteria and labeled with biotin could also bind alphaDG on the membrane blot, and the unlabeled fragment disrupted the binding of biotin-laminin-1 to alphaDG. The interaction of biotin-laminin-1 with alphaDG was inhibited by soluble alphaDG contained in the conditioned medium from DG cDNA-transfected BAE cells and by a series of glycosaminoglycans (heparin, dextran sulfate, and fucoidan). Soluble alphaDG in the conditioned medium inhibited the adhesion of BAE cells to laminin-1-coated dishes, whereas it had no effect on their adhesion to fibronectin. All three glycosaminoglycans that disrupted the biotin-laminin-1 binding to alphaDG inhibited BAE cell adhesion to laminin-1, whereas they failed to inhibit the adhesion to fibronectin. These results indicate a role of DG as a non-integrin laminin receptor involved in vascular endothelial cell adhesion to the extracellular matrix.
We previously reported that endogenous angiotensin II is released to cause mitogen-activated protein (MAP) kinase stimulation in the media portion of the vasculature. In this study, we examined whether a functional renin-angiotensin system is indeed present within the media of the vasculature. In rat aortic strips, endothelium removal produced an increase of MAP kinase activity. The MAP kinase activation was inhibited either by the renin inhibitor pepstatin A or by the angiotensin-converting enzyme inhibitor captopril. The degree of the inhibition of the MAP kinase activation by pepstatin A, captopril and the angiotensin receptor antagonist losartan was almost the same. Pepstatin A inhibited MAP kinase activation induced by renin but not by angiotensin I and angiotensin II. Captopril inhibited the MAP kinase activation induced by angiotensin I but not by angiotensin II. In nephrectomized rat aortic strips, endothelium removal also produced an increase in MAP kinase activity, but the MAP kinase activation was considerably small and minimally inhibited by losartan. Nephrectomy produced a marked decrease in plasma renin activity. These findings suggest that an apparently fully intact and functional renin-angiotensin system is present in the media of the rat vasculature and this system serves to increase MAP kinase activity. It appears that renin plays the determining role in the regulation of angiotensin generation also in the media and the major source of the renin is renin of kidney origin.
CD36 and LIMPII analogous-1 (CLA-1), a human homolog of the rodent scavenger receptor B1 (SR-B1), binds high-density lipoprotein (HDL) and mediates the selective uptake of HDL cholesterol ester (CE) by cultured transfected cells. CLA-1 is strongly expressed in steroidogenic tissues, including the adrenal gland, suggesting that CLA-1 plays a role in providing substrates for steroidogenesis. To address this, we established an adrenocortical cell line that highly expresses CLA-1. These cells increased CE uptake from HDL to 140.5% of the level in mock-transfected cells. After incubation of the transfected cells with HDL, corticosterone secretion from CLA-1-transfected cells increased to about two times the level in mock-transfected cells. These results indicate the possibility that CLA-1 (a close structural homolog of SR-B1)-mediated uptake of HDL CE may be a significant source of precursor cholesterol for steroidogenesis in humans as it is in mice.