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Biomedical subjects

R Nagai

Publications and source records attributed to R Nagai.

At least 19 recordsLinked to original sources
PubMed1998

Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein.

Inactivation of the klotho (kl) gene in mice results in multiple disorders that resemble human aging. The mouse kl gene encodes a novel single-pass membrane protein with homology to beta-glucosidases. In this study, we have isolated a human homologue of the kl gene and determined its gene structure. The human kl gene is composed of 5 exons and ranges over 50 kb on chromosome 13q12. We have further identified two transcripts that encode a membrane or secreted protein. These transcripts arise from a single kl gene through alternative RNA splicing. Expression of the putative secreted form predominates over that of the membrane form. The present study provides fundamental information necessary for further analyses of the human kl gene and its functions.

Aging↗
PubMed1998

Effects of renal perfusion pressure on renal interstitial hydrostatic pressure and Na+ excretion: role of endothelium-derived nitric oxide.

The purpose of this study was to examine the role of endothelium-derived nitric oxide in modulating the effect of renal perfusion pressure (RPP) on renal interstitial hydrostatic pressure (RIHP) and urinary Na+ excretion (UNaV). The effects of RPP on renal hemodynamics, RIHP, and Na+ and Li+ excretions were determined in control Sprague-Dawley rats, in Sprague-Dawley rats pretreated with intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME) at doses of 1, 5, and 50 microg/kg/min, and in rats pretreated with L-NAME (5 microg/kg/min) plus L-arginine (10 mg/kg/min). The RPP was changed from 95 to 135 mm Hg by an electronically servo-controlled aortic occluder above the renal arteries in all groups. Increasing RPP in control rats from 95 to 135 mm Hg increased RIHP (from 4.4 +/- 0.5 to 8.7 +/- 1.2 mm Hg), UNaV (from 2.37 +/- 0.61 to 8.29 +/- 1.59 microEq/min), and fractional excretion of Li+ (from 38.0 +/- 2.5 to 51.4 +/- 6.0%). In rats pretreated with L-NAME (5 microg/kg/min), increases in RPP from 95 to 135 mm Hg had no effect on RIHP (from 1.6 +/- 0.4 to 2.2 +/- 0.6 mm Hg) or fractional excretion of Li+ and markedly attenuated pressure-natriuresis relationship (from 1.84 +/- 0.50 to 2.88 +/- 0.65 microEq/min). Although L-NAME did reduce renal plasma flow and glomerular filtration rate, the autoregulatory responses to RPP were maintained. In rats pretreated with L-NAME plus L-arginine, RIHP, UNaV, and fractional excretion of Li+ responses to RPP were similar to the control rats. The results of this study indicate that endothelium-derived nitric oxide plays an important role in modulating the effect of RPP on Na+ excretion by enhancing the transmission of RPP into the renal interstitium.

Animals↗
PubMed1998

Efficient inhibition of the development of cardiac remodeling by a long-acting calcium antagonist amlodipine.

The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of "fetal type" genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of beta-myosin heavy chain, skeletal alpha-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively prevented cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.

Amlodipine↗
PubMed1998

Decreased basal production of nitric oxide in patients with heart disease.

STUDY OBJECTIVES: The pathophysiologic role of nitric oxide (NO) released in the lung is not well understood. To determine whether the production of endogenous NO is correlated with any hemodynamic parameters, we measured the amount of NO released from the lung tissue of patients with heart disease. METHODS: Twenty patients (14 with ischemic heart disease, 4 with dilated cardiomyopathy, and 2 with mitral stenosis) and 16 normal control subjects were enrolled in the study. We measured exhaled air samples by using a method developed in our laboratory. The NO release rate from the lungs was calculated from the amount of exhaled NO and the duration of the exhalation. RESULTS: The rate of NO release was significantly lower in the patients with moderate-to-severe heart failure (New York Heart Association [NYHA] II or III) than in those with mild heart failure (NYHA I) or in normal control subjects. The rate of NO release was positively correlated with the cardiac index (r=0.50, p<0.05), and was negatively correlated with either the systemic (r= -0.58, p<0.01) or pulmonary vascular resistance (r=-0.45, p<0.05). In the patients with moderate-to-severe heart failure, the amount of NO released and the oxygen tension in the pulmonary artery were significantly lower compared with those parameters in patients with mild heart failure. CONCLUSIONS: Results suggest that the basal production of endogenous NO in the lung tissue of patients with heart failure is impaired, perhaps leading to the elevated pulmonary vascular tone seen in patients with moderate-to-severe heart failure.

Adult↗
PubMed1997

Mutation of the mouse klotho gene leads to a syndrome resembling ageing.

A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.

Aging↗
PubMed1997

Isolation of the embryonic form of smooth muscle myosin heavy chain (SMemb/NMHC-B) gene and characterization of its 5'-flanking region.

To examine the molecular mechanisms that regulate the expression of the SMemb/NMHC-B gene, a nonmuscle myosin heavy chain isoform predominantly expressed in fetal aorta, we have isolated and characterized the 5'-flanking region of the rabbit SMemb/NMHC-B gene. Transient transfection experiments demonstrated that 105 base pairs of 5'-flanking sequence was necessary to direct high level transcription in C2/2 cells, vascular smooth muscle cells derived from rabbit aorta. An essential cis-regulatory element was localized between -100 and -91 base pairs from the transcription start site based on the results that replacement mutagenesis within this region significantly reduced promoter activity. Sequence of this region is completely conserved between mouse and rabbit and fits no known DNA binding consensus. Gel mobility shift assays revealed that a specific DNA-protein complex was formed at this site with nuclear extracts from C2/2 cells, which can be competed by H-2Kb CCAAT box but not by Hsp70 CCAAT box or other CCAAT-containing sequences. We conclude that expression of the SMemb/NMHC-B gene is regulated through an interaction between a sequence element located at -100 and a distinct member of CCAAT-binding proteins.

3T3 Cells↗
PubMed1997

Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.

When hypertrophic growth is induced in neonatal rat cardiocytes by stretching, the cardiocytes express high levels of brain-type natriuretic peptide (BNP) and the proprotein-processing enzyme furin. A BNP precursor, gammaBNP, possesses a furin-cleavable Arg-X-X-Arg motif, which is cleaved when gammaBNP is processed to form BNP-45. The Arg-X-X-Arg motif is found in many precursors of growth factors and growth-related proteins. To determine if furin converts gammaBNP to BNP-45 as well as other unidentified growth-promoting protein precursors to their active form that may induce hypertrophic growth in cardiocytes, we used two protease inhibitor systems, synthetic peptidyl chloromethyl ketones (CMK) (dec-Arg-Val-Lys-Arg-CMK and dec-Phe-Ala-Lys-Arg-CMK; where dec is decanoyl) and vaccinia vector-integrated native and variant alpha1-antitrypsins. The furin-specific inhibitors, dec-Arg-Val-Lys-Arg-CMK and variant alpha1-antitrypsin with the inhibitory determinant Arg-X-X-Arg, suppressed the stretch-induced hypertrophic growth of cardiocytes as well as the processing of gammaBNP to BNP-45. The other serine protease inhibitors and variant alpha1-antitrypsin against elastase, or thrombin, however, neither suppressed the hypertrophic growth nor prevented the processing of gammaBNP to BNP-45. Thus, we suggest that furin catalyzes the conversion of gammaBNP to BNP-45 as well as growth-promoting proproteins to their active form, which might induce hypertrophic growth in cardiocytes.

Animals↗
PubMed1997

Redifferentiation of smooth muscle cells after coronary angioplasty determined via myosin heavy chain expression.

BACKGROUND: The pathophysiology of phenotypic modulation of smooth muscle cells (SMCs) involved in restenosis after angioplasty is not well understood. Smooth muscle myosin heavy chain (SM MHC) isoforms (SM1 and SM2) are specific markers for SMC differentiation. In particular, SM2 is useful as a marker of mature SMCs. SMemb is a nonmuscle myosin heavy chain (NM MHC) whose expression is upregulated in immature or activated SMC. METHODS AND RESULTS: To determine SMC phenotypes in neointimal tissues after percutaneous transluminal coronary angioplasty (PTCA), we performed immunohistochemistry on human coronary arteries with antibodies against alpha-SM actin, SM1, SM2, and SMemb. Tissues were obtained from six autopsied patients and from atherectomy specimens from 16 patients who had undergone PTCA. Medial SMCs were positive for alpha-actin, SM1, and SM2. Expression of SM1 and SM2 in the neointima varied with the time after intervention, whereas alpha-actin was constitutively expressed in all cases studied. Neointimal cells at 16 and 20 days after PTCA contained alpha-actin but little or no SM1 or SM2, indicating that these cells modulated their phenotype to the immature state. Neointimal SMCs recovered SM MHC expression, first SM1 and then SM2, by 6 months after PTCA. Increased expression of SMemb was found in the neointima but without apparent relationship to the time after PTCA. CONCLUSIONS: Neointimal SMCs show features of an undifferentiated state, indicated by altered expression of SM MHC, and undergo redifferentiation in a time-dependent manner. The expression of SM MHC isoforms provides insight into the biology of healing after angioplasty and furnishes useful tools for the understanding of the roles of differentiation and phenotypic modulation of SMCs in human vascular lesions.

Aged↗
PubMed1997

Hydroxyl radical mediates N epsilon-(carboxymethyl)lysine formation from Amadori product.

Recent studies demonstrated N epsilon-(carboxymethyl)lysine (CML) in several tissue proteins. Incubation of proteins with glucose leads through a Schiff base to Amadori products. Oxidative cleavage of Amadori products is considered as a major route to CML formation in vivo, whereas it is not known which reactive oxygen species (ROS) is involved. The present study is undertaken to identify such a ROS. We prepared heavily glycated human serum albumin (HSA) which contained a high level of Amadori products, but an undetectable level of CML. Incubation of glycated HSA with FeCl2, but not with H2O2, led to CML formation which was enhanced by H2O2, but inhibited by catalase or mannitol, whereas superoxide dismutase had no effect. Similar data were obtained by experiments using Boc-fructose-lysine as a model Amadori compound. These data indicate that hydroxyl radical generated by the reaction of Fe2+ with H2O2 mediates CML formation from Amadori compounds.

Catalase↗
PubMed1997

Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.

BACKGROUND: Familial long-QT syndrome (LQTS) is characterized by prolonged ventricular repolarization. Clinical symptoms include recurrent syncopal attacks, and sudden death may occur due to ventricular tachyarrhythmias. Three genes responsible for this syndrome (KVLQT1, HERG, and SCN5A) have been identified so far. We investigated mutations of these genes in LQTS families. METHODS AND RESULTS: Thirty-two Japanese families with LQTS were brought together for screening for mutations. Genomic DNA from each proband was examined by the polymerase chain reaction-single-strand conformation polymorphism technique followed by direct DNA sequencing. In four of the families, comprising 16 patients, mutations were identified in KVLQT1; five other families (9 patients) segregated mutant alleles of HERG. All 25 of these patients carried the specific mutations present in their respective families, and none of 80 normal individuals carried these alleles. Mutations were confirmed by endonuclease digestion or hybridization of mutant allele-specific oligonucleotides. No mutation in SCN5A was found in any family. CONCLUSIONS: We identified nine different mutations among 32 families with LQTS. Eight of these were novel and account for 25% of all types of mutations reported to date. Such a variety of mutations makes it difficult to screen high-risk groups using simple methods such as endonuclease digestion or mutant allele-specific amplification.

Alleles↗
PubMed1997

Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease furin after myocardial infarction in rats.

We investigated the expression of the yeast Kex2 family endoproteases furin and PACE4, and brain natriuretic peptide (BNP) in the atrium and ventricle after infarction as well as the conversion of the BNP precursor gammaBNP to BNP-45. In a rat heart failure model, plasma BNP rose in two phases--first at day 3, and again at day 14. BNP mRNA, as measured by Northern blot analysis, increased strongly at day 3, then at days 14 and 28 less strongly in the atrium, and in the ventricle it increased weakly at day 3, then strongly at days 14 and 28. Furin mRNA showed the same pattern of expression as that of BNP message, whereas PACE4 message stayed unchanged after the infarction. Both furin and BNP were immunostained in the myocardium adjacent to the infarcted tissue. We suggest that after myocardial infarction, furin is co-expressed with BNP in both the atrium and ventricle, and that furin may be responsible for the conversion of gammaBNP to BNP-45.

Animals↗
PubMed1997

The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas.

Both advanced glycation end products and vascular endothelial growth factor are believed to play a role in the pathogenesis of diabetic retinopathy. It is known that vascular endothelial growth factor causes retinal neovascularization and a breakdown of the blood-retinal barrier; how advanced glycation end products affect the retina, however, remains largely unclear. The substance-Ne-(carboxymethyl)lysine is a major immunologic epitope, i.e. a dominant advanced glycation end products antigen. We generated an anti-Ne-(carboxymethyl)lysine antibody to investigate the relationship between the localization of advanced glycation end products and that of vascular endothelial growth factor in 27 human diabetic retinas by immunohistochemistry. Nine control retinas were also examined. In all 27 diabetic retinas, Ne-(carboxymethyl)lysine was located in the thickened vascular wall. In 19 of the 27 retinas, strand-shaped Ne-(carboxymethyl)lysine immunoreactivity was also observed around the vessels. In all 27 diabetic retinas, vascular endothelial growth factor revealed a distribution pattern similar to that of Ne-(carboxymethyl)lysine. Vascular endothelial growth factor was also located in the vascular wall and in the perivascular area. Neither Ne-(carboxymethyl)lysine nor vascular endothelial growth factor immunoreactivity was detected in the 9 control retinas. Vessels with positive immunoreactivity for Ne-(carboxymethyl)lysine and/or vascular endothelial growth factor were counted. A general association was noted between accumulation of Ne-(carboxymethyl)lysine and expression of vascular endothelial growth factor in the eyes with non-proliferative diabetic retinopathy (p < 0.01) and proliferative diabetic retinopathy (p < 0.05).

Aged↗
PubMed1997

Ventilation/perfusion ratios and simultaneous dual-radionuclide single-photon emission tomography with krypton-81m and technetium-99m macroaggregated albumin.

To date, there has been neither a good method to clarify the three-dimensional distribution of pulmonary ventilation/perfusion (V. A/Q.) ratios, nor a convenient way to assess V.A/Q. inequality. The purpose of this study was to develop a functional image of pulmonary V.A/Q. ratios based on data acquired with simultaneous dual-radionuclide single-photon emission tomography (SPET) and to assess V.A/Q. unevenness through the V.A/Q. histogram in patients with various pulmonary diseases. Dual-radionuclide SPET was performed with technetium-99m macroaggregated albumin (MAA) and krypton-81m, with the patient in the supine position. After correction for linear cross-talk, the total acquisition counts of both radionuclides were equalized. The V.A/Q. ratio, which was calculated in each pixel by dividing the 81mKr count by the 99mTc-MAA count, was expressed as a V.A/Q. image. A histogram of the pixel number plotted against the V.A/Q. ratios was then produced and its centre of weight (CW) and standard deviation (SD) determined. Ten healthy volunteers and 46 patients [seven with pulmonary vascular disease (PVD), nine with pulmonary emphysema (PE), 18 with bronchogenic carcinoma and 12 with miscellaneous diseases] participated in this study. In normal volunteers, V.A/Q. ratios were generally even, but were slightly lower in dorsal regions. Patients with PVD had lobar and/or segmental areas with a high V.A/Q. ratio. Low V.A/Q. areas extended widely in patients with PE. Bronchogenic carcinoma exceeding 3 cm in diameter was detected as a very low V. A/Q. area. The SD of V.A/Q. ratios had a significant positive correlation both with A-aDO2 (r=0.64, P<0.001) and with cigarette smoking history (r=0.72, P<0.001). It is concluded that the V.A/Q. ratio image produced with simultaneous dual-radionuclide SPET using 99mTc-MAA and 81mKr is a unique and simple method for demonstrating the three-dimensional distribution of V.A/Q. ratios. The unevenness of V.A/Q. distribution can be assessed through the SD of the V.A/Q. histogram.

Adult↗
PubMed1997

[Increased serum concentration of myosin heavy chain in aortic dissection: discussion of 2 cases].

Despite the availability of diagnostic modalities such as transesophageal echocardiography, computed tomography or magnetic resonance imaging up to 30% of patients with acute aortic dissection remain undiagnosed before death. A novel immunoassay of serum smooth muscle myosin heavy chain was recently developed as a potential diagnostic tool for the detection of aortic dissection. The immunoassay was applied in two patients with an acute chest pain syndrome but no initial clinical suspicion of aortic disease. In both patients myocardial ischemia was ruled out by laboratory, electrocardiographic and echocardiographic examinations. In the first patient both dilation of the aorta and long-standing arterial hypertension were known; however, it was not before 48 h until dissection was suspected and a spiral-CT was performed demonstrating a localized ascending aortic dissection. At this time (48 h after onset of symptoms) the smooth muscle myosin heavy chain concentration in the serum was close to normal. In the other patient there was neither a suggestive history nor any clinical sign of aortic dissection. Widening of the abdominal aortic wall on an ultrasound examination was the key to the incidental diagnosis of a clinically unsuspected type B dissection. The serum test 12 h after onset of pain revealed elevated (diagnostic) serum levels of smooth muscle myosin heavy chains. Both cases exemplify important gaps in the diagnostic strategy for the detection of acute aortic dissection. A novel immunoassay for smooth muscle myosin heavy chains provides rapid and reliable diagnostic information especially in patients without clinically suspected aortic dissection and may avoid limitations in the diagnostic work-up of patients with acute aortic disease, if used early in the evaluation of patients with chest pain syndromes.

Aged↗
PubMed1997

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: pathogenesis of impaired acidification.

Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification has a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH4+) excretion was low at 11 mumol/min per 1.73 m2; fractional excretion of bicarbonate HCO3 (FEHCO3) was high at 9% when plasma HCO3 was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FEHCO3 of 14%, a urine-blood PCO2 difference of 7 mmHg, NH4+ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FEHCO3 to fall to 0, the NH4+ excretion rate to rise to 43 mumol/min per 1.73 m2, and citrate excretion to fall to < 0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH4+ excretion, a low urine minus blood PCO2 difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CAII deficiency.

Acidosis, Renal Tubular↗
PubMed1997

Pulmonary expression of vascular endothelial growth factor and myosin isoforms in rats with congenital diaphragmatic hernia.

Abnormalities of the pulmonary vasculature are well documented in cases of congenital diaphragmatic hernia (CDH). Vascular endothelial growth factor (VEGF), an angiogenic factor, is a recently described endothelial cell-specific growth factor. Myosin heavy chain (MHC) isoforms such as SMemb, SM1 and SM2 are important molecular markers used to study vascular smooth muscle cell differentiation. SMemb is predominantly expressed in immature smooth muscle cells (SMC), and SM2 is expressed in mature SMCs. The authors investigated the expression of VEGF and SMC differentiation in pulmonary vessels in CDH rat lungs and in controls. The lungs of nitrofen-induced CDH rat fetuses (n = 16, gestational age 16, 18, 20, and 22 days) were stained immunohistochemically using antibodies against VEGF, SMemb and SM2, while alpha-actin was used as a general marker of vascular smooth muscle cells. In the CDH group VEGF expression was negative in pulmonary vessels before birth, and in the control group VEGF was positive in smooth muscle cells in vessel walls from 20 days both in vessels at the hilum and in pulmonary parenchyma. In both control and CDH groups, SMemb expression was positive from 16 days' gestation. SM2 expression was negative in vessel walls during the prenatal period in both groups. Alpha-actin was localized in both lungs obtained from control and CDH groups in the lung hilum from 16 days and around peripheral vessels from 18 days. Differences in vascular smooth muscle cell differentiation were not observed between control and CDH lung. These findings suggest that differences in pulmonary vascular development exist between control and CDH rats for VEGF expression, and maturational differences in smooth muscle cell differentiation are not present. This role of altered endothelial cell growth might be related to the different pulmonary vascular reactivity present in CDH lungs.

Animals↗
PubMed1997

Proliferation of smooth muscle cells in acute allograft vascular rejection.

OBJECTIVES: To determine whether immune injury during acute cardiac rejection induces phenotypic modulation of arterial smooth muscle cells and lesion formation, we studied the expression of embryonic myosin heavy-chain isoform and degrees of intimal proliferation in aortas and coronary arteries of allografted rabbit hearts. Modulation of phenotype in arterial smooth muscle cells during acute vascular injury is a widely reported phenomenon, and proliferation and migration of medial smooth muscle cells contribute to development of intimal hyperplasia of arteries in response to immune injury. METHODS: Rabbit hearts were heterotopically transplanted to the neck without immunosuppression. Hearts were harvested at 2, 5, 7, and 10 days after transplantation. Proliferation of smooth muscle cells was assessed by bromodeoxyuridine labeling. Staining for immunohistochemical indicators was done with use of monoclonal antibodies that recognize T lymphocytes and all types of smooth muscle cells (SM1), adult type of smooth muscle cells (SM2), and embryonic myosin heavy-chain isoform. Intimal thickening and luminal narrowing were assessed with a computer-assisted video image analysis system. RESULTS: Intimal thickening and luminal narrowing in aortas and coronary arteries gradually increased in a time-dependent manner. The neointima thus formed consisted of proliferating smooth muscle cells positive for both SM1 and embryonic myosin heavy-chain isoform and massive T lymphocyte accumulation. Intimal proliferation was more prominent in aortas and large epicardial coronary arteries than in the intramyocardial small coronary arteries. CONCLUSIONS: These findings suggest that allogeneic immune injury facilitates phenotypic modulation of smooth muscle cells, which may contribute to subsequent transplantation-associated atherosclerosis.

Animals↗