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Results for “Phenotypic modulation”

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At least 271 records · Page 15Linked to original sources

PubMed2004

Perivascular delivery of losartan with surgical fibrin glue prevents neointimal hyperplasia after arterial injury.

OBJECTIVE: Long-term success of revascularization procedures is limited by recurrent stenosis, a reduction in vascular lumen area that results from neointimal hyperplasia. Inhibitors of the renin-angiotensin system, such as losartan, have potential to prevent recurrent stenosis; however, to date, efficacy has not been demonstrated in either animal models or human beings. While we have previously reported that treatment with a satisfactory dose may be an important element in obtaining efficacy, oral delivery cannot achieve the required concentration. We therefore tested the ability of losartan to restrict neointimal hyperplasia after local delivery of an elevated dose in a fibrin glue. METHODS: The porcine saphenous artery was subjected to balloon angioplasty. Losartan (25 micromol/mL) was applied directly to the adventitial surface of the injured vessel after mixing with 1.0 mL of Tisseel. Neointimal formation was quantified after 14 days with morphometry, and immunologic staining was used to monitor expression of proteins associated with cell proliferation, migration, and phenotypic modulation. RESULTS: A statistically significant decrease of 82% (n = 5) in neointimal area was obtained with losartan, and cell proliferation, as defined by proliferating cell nuclear antigen (PCNA) expression, was inhibited by 97%. Reduced cyclin A expression in losartan-treated vessels confirmed that cell cycle progression was blocked; however, the presence of cytokeratin 8 and tenascin in the media and neointima of injured vessels, regardless of treatment, suggested that losartan does not restrict phenotypic modulation. Inhibition of MT1-MMP (MMP-14) expression by losartan indicated that this inhibitor likely suppresses cell migration as well. CONCLUSIONS: These data demonstrate that losartan can effectively prevent recurrent stenosis when delivered locally with a fibrin glue such as Tisseel. Our results also indicate that losartan may operate by interfering with the expression of proteins required for cell cycle progression and migration. CLINICAL RELEVANCE: Release of angiotensin II in response to vascular injury may promote neointimal hyperplasia, because this hormone can stimulate smooth muscle cell proliferation and migration. This study demonstrates that local application of an angiotensin receptor antagonist, losartan, to the site of injury can effectively prevent neointimal hyperplasia after balloon angioplasty. Application of losartan to the perivascular surface of the injured vessel in a surgical fibrin glue enabled delivery of a dose that exceeds the maximum attainable, via a systemic delivery route. The glue also served as a depot from which the drug was slowly released over time. Treatment with losartan may be a viable approach for controlling neointimal hyperplasia at locations (eg, grafts) that are accessible during a surgical procedure.

Administration, Topical↗

PubMed1995

Cardiac hypertrophy-related gene expression in spontaneously hypertensive rats: crucial role of angiotensin AT1 receptor.

Angiotensin converting-enzyme inhibitors (alacepril and imidapril) or an AT1-receptor antagonist (SC-52458) was administered to 10-week-old spontaneously hypertensive rats (SHR) for 7 days, and cardiac mRNA levels for contractile proteins and atrial natriuretic polypeptide (ANP) were comprehensively measured. The expression of skeletal alpha-actin and ANP was selectively enhanced in the heart of vehicle-treated SHR compared with Wistar-Kyoto rats (WKY), thereby suggesting that the phenotypic modulation of myocytes occurred at the early stage of hypertension. The above-mentioned three drugs similarly suppressed these enhanced gene expressions, nearly to the control levels. In contrast, although the treatment with hydralazine lowered the blood pressure of SHR similarly, hydralazine did not suppress ANP expression at all and only partially suppressed skeletal alpha-actin. Moreover, alacepril did not affect these gene expressions in WKY. Thus, AT1 receptor may be crucial for phenotypic modulation in the heart of SHR.

Angiotensin Receptor Antagonists↗

PubMed1997

Effects of the medium conditioned by endothelial cells under hypoxic condition on the phenotype of porcine pulmonary arterial smooth muscle cells.

The effects of the medium conditioned by endothelial cells under hypoxic condition on the phenotype modulation of pulmonary artery smooth muscle cells (PASMCs) were investigated by using cell culture and morphometrical analysis. The results showed that the number of diploid cells and alpha-sm-actin of PASMCs in the hypoxic endothelial cell conditioned medium group (HECCM) was lower and the myofibrilles were even less than that in normal endothelial cell conditioned medium group (NECCM). On the contrary, the volume density of rough endoplasmic reticulum (RER) and mitochondria of PASMCs in the HECCM group was higher than that in the NECCM group, i.e. altering from a contractile type to a synthetic type. However, under direct hypoxic condition for 24 h, the phenotype of cultured PASMCs remained unchanged, i.e. retained contractile type. It suggests that the HECCM can induce phenotype modulation of PASMCs, may be mediated by the pulmonary artery endothelial cells (PAECs) which can secrete some cytokins affecting the PASMCs.

Animals↗

PubMed2006

Hyperplasia suppressor gene associates with smooth muscle alpha-actin and is involved in the redifferentiation of vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation are characterized by changes in gene expression for smooth muscle (SM) marker contractile proteins such as SM alpha-actin and SM22alpha. Hyperplasia suppressor gene (HSG) is a potent VSMC proliferation-inhibiting factor; however, it is not known if HSG is involved in the redifferentiation of VSMCs. Here, the redifferentiation of the dedifferentiated VSMCs was induced by serum withdrawal or all-trans retinoic acid (atRA), HSG gene expression and its role in VSMC phenotypic modulation were studied by reverse transcription - polymerase chain reaction, Western blotting, and cell migration assay. The results indicated that HSG gene expression increased significantly during VSMC redifferentiation induced by serum deprivation or atRA and peaked at 24 h, then was maintained at higher levels. Meanwhile, SM marker contractile proteins SM alpha-actin and SM22alpha were increased by more than 2-fold. Coimmunoprecipitation and immunofluorescent experiments revealed that anti-HSG antibody could precipitate SM alpha-actin, and HSG and SM alpha-actin colocalized within the cytoplasm of differentiated VSMCs. Migration activity of VSMCs was dramatically suppressed after cells were transfected with HSG expression plasmids. These findings suggested that HSG is associated with SM alpha-actin in VSMC cytoplasm, and is involved in VSMC differentiation and migration.

Actins↗

PubMed2003

[Cardiovascular research in the era of genome medicine and EBM].

In the postgenome era, medical science should aim at elucidating the physiological functions as well as pathophysiological roles of genetics in a variety of diseases. The latter is especially important in clinical medicine for investigating the biological background of diseases. The cardiovascular system undergoes phenotypic modulation in response to environmental factors such as hemodynamic stress, aging, inflammation, and various life style influences including smoking and obesity. We have been focusing on transcriptional mechanisms by which cardiovascular cells change the profiles of gene expression in response to metabolic and mechanical stresses. We isolated a DNA-binding factor, Krüppel-like factor 5 (KLF5), as a transcription factor of the embryonic isoform of smooth muscle myosin heavy chain gene(SMemb), whose expression is induced in phenotypically modulated smooth muscle cell and cardiac fibroblasts. Recently, by developing KLF5 gene knockout mice, we have found that KLF5 is an essential regulator of cardiovascular remodeling. We have further found that differential chemical modifications and protein-protein interactions regulate this family of factors. To understand genome functions in the pathogenesis of cardiovascular diseases, we are constructing an original database system by filing complicated clinical parameters for genetic association studies. DNA samples obtained from the participants have reached approximately one thousand. Using them, we have analyzed over 50 genetic polymorphisms implicated in atherosclerotic diseases. Among the many SNPs analyzed in our study, we have shown that polymorphisms in the MMP-1 and MMP-3 promoters are associated with disease susceptibility to myocardial infarction.

Evidence-Based Medicine↗

PubMedDate not supplied

Reduction in Gh protein expression is associated with cytodifferentiation of vascular smooth muscle cells.

Gh, a high molecular weight GTP-binding protein that couples alpha 1-adrenoceptors in heart and liver to phosphatidylinositol (PtdIns)-specific phospholipase C (PLC), has recently been shown to be a tissue transglutaminase type II. Transglutaminases have been suggested to play a role in the maintenance of blood vessel structure, and therefore it is possible that changes in their expression may accompany pathological states which involve phenotypic modulation of smooth muscle. Hence, we investigated the expression of Gh during differentiation of rat aortic smooth muscle cells in culture. Gh content was reduced markedly in cultured smooth muscle cells compared to freshly isolated cells as determined by Western blotting using a Gh-specific monoclonal antibody. In contrast, the level of Gq, a heterotrimeric G-protein that couples alpha 1-adrenoceptors to PLC, was maintained throughout the culture period. These findings indicate that changes in Gh expression accompany phenotypic modulation of vascular smooth muscle cells. These changes in Gh protein expression may be important in the altered responsiveness of vessels in pathological disease states.

Amino Acid Sequence↗

PubMed2005

Modulation of phenotype and function of dendritic cells by a therapeutic synthetic killer peptide.

The strong microbicidal effects of an engineered synthetic killer peptide (KP), which functionally mimics a fungal killer toxin, have been demonstrated extensively. Beta-glucan has been identified as a receptor for KP on fungal cell walls. Although the direct microbicidal and related therapeutic effects have been studied in depth, no information currently exists about the interaction of KP with immune cells. In this study, we exploited the possibility of KP binding to different murine immune cell populations. The results demonstrate that KP binds selectively to dendritic cells (DC) and to a lesser extent, to macrophages but not to lymphocytes and neutrophils; KP binding possibly occurs through major histocompatibility complex (MHC) class II, CD16/32, and cellular molecules recognized by anti-specific intercellular adhesion molecule-grabbing nonintegrin R1 antibodies; and KP modulates the expression of costimulatory and MHC molecules on DC and improves their capacity to induce lymphocyte proliferation. These findings provide evidence that this synthetic KP interacts selectively with DC and modulating their multiple functions, might also serve to improve the immune antimicrobial response.

Animals↗

PubMed2002

Importance of NAD(P)H oxidase-mediated oxidative stress and contractile type smooth muscle myosin heavy chain SM2 at the early stage of atherosclerosis.

BACKGROUND: Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22(phox) expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections. METHODS AND RESULTS: Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22(phox) and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups. CONCLUSIONS: These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.

Actins↗

PubMed2006

Differing influence of sympathectomy on smooth muscle cells and fibroblasts in cerebral and peripheral muscular arteries.

In the present study, we examined the effect of sympathectomy on the distribution and the relative expression of cytoskeletal proteins used as markers of phenotypic modulation of vascular smooth muscle cells (SMCs) and myofibroblasts (MFBs) in rabbit femoral (FA) and basilar (BA) arteries. Adult rabbits were treated either with repeated 6-hydroxydopamine (6-OHDA) for sympathectomy or with vehicle for control. Cross sections taken from sympathectomized and control arteries 79 days later were immunolabelled for vimentin, desmin, alpha-smooth muscle actin (alpha-SM actin), beta-isoform of actin and h-caldesmon. The distribution of these proteins and the intensity of fluorescent labelled SMCs were examined under a confocal microscope. In the sympathectomized BA, there was no change for desmin, vimentin and h-caldesmon expression, but the expression of both alpha-SM actin and the beta-isoform was significantly higher (+19% and +30%, respectively). In the sympathectomized FA, the expression of the alpha- and beta-isoforms of actin remained unchanged, whereas those of desmin and vimentin were significantly higher (+35% and 17%, respectively) and h-caldesmon expression was lowered by 13%. In contrast to intact FAs, the external layers of sympathectomized FAs revealed migration of fibroblasts from the adventitia and death of SMCs. These results strongly suggest that sympathetic nerves intervene in the cytoskeletal protein remodelling through phenotypic modulation of both SMCs and MFBs during post-natal development, and in pathologies involving similar phenomena, such as atherosclerosis.

Animals↗

PubMed1995

Transcriptional regulation of the chicken caldesmon gene. Activation of gizzard-type caldesmon promoter requires a CArG box-like motif.

Caldesmon, which plays a vital role in the actomyosin system, is distributed in smooth muscle and non-muscle cells, and its isoformal interconversion between a high M(r) form and low M(r) form is a favorable molecular event for studying phenotypic modulation of smooth muscle cells. Genomic analysis reveals two promoters, of which the gizzard-type promoter displays much higher activity than the brain-type promoter. Here, we have characterized transcriptional regulation of the gizzard-type promoter. Transient transfection assays in chick gizzard smooth muscle cells, chick embryo fibroblasts, mouse skeletal muscle cell line (C2C12), and HeLa cells revealed that the promoter activity was high in smooth muscle cells and fibroblasts, but was extremely low in other cells. Cell type-specific promoter activity depended on an element, CArG1, containing a unique CArG box-like motif (CCAAAAAAGG) at -315, while multiple E boxes were not directly involved in this event. Gel shift assays showed the specific interaction between the CArG1 and nuclear protein factors in smooth muscle cells and fibroblasts. These results suggest that the CArG1 is an essential cis-element for cell type-specific expression of caldesmon and that the function of CArG1 might be controlled under phenotypic modulation of smooth muscle cells.

Animals↗

PubMed2005

[Expression of cellular repressor of E1A-stimulated genes in vascular smooth muscle cells of different phenotypes].

OBJECTIVES: The phenotypic modulation of vascular smooth muscle cells (VSMC) plays a central role in the pathogenesis of arteriosclerosis. The purpose of this study was to investigate the expression of the cellular repressor of E1A-activated genes (CREG) at the transcriptional and protein level in human internal thoracic artery smooth muscle cells (HITASY), which express different patterns of differentiation markers after serum withdrawal. METHODS: After cloning and recombining the CREG vector, the antiserum against the CREG protein was produced from the rabbits immunized by the purification CREG protein. The specificity of purified polyclonal antibody was detected by Western blot assay. The DNA synthesis of HITASY cultured in serum-free and serum-supplemented medium was measured by the [(3)H]-thymidine incorporation. Western blot analysis detected the expression of smooth muscle-specific markers (smooth muscle alpha-actin, calponin). The localization of CREG in cells was examined with immunohistochemistry staining and expression of CREG mRNA and protein were analyzed by RT-PCR and Western blot in HITASY after serum withdrawal. RESULTS: The high specificity of polyclonal antibody against CREG obtained from rabbits was confirmed by Western blot assay. In response to serum withdrawal, cultured HITASY cells exhibited phenotypic conversion from synthetic into contractile one as evidenced by the data of [(3)H]-thymidine incorporation and Western blot. The DNA synthesis of HITASY precipitously dropped to background levels after serum withdrawal and nearly restored after reintroduction of serum to culture medium 2 days later. Western blot revealed a reversible upregulation of smooth muscle alpha-actin and calponin in HITASY after serum deprivation. Moreover, serum withdrawal also induced a prominent increase of CREG mRNA and protein expression which reached a peak on 3 days and decreased gradually on 5 approximately 7 days after serum withdrawal. Immunohistochemistry stain indicated the CREG protein mainly localizes in a perinuclear pattern in HITASY cells. CONCLUSIONS: Those data provide evidence that the coordinated changes in CREG gene and protein expression as well as smooth muscle-specific markers may take place in connection with the process of phenotypic modulation of VSMC in vitro.

Actins↗

PubMed2003

KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates both smooth muscle cell activation and cardiac hypertrophy.

Cardiac and vascular biology need to be approached interactively because they share many common biological features as seen in activation of the local renin-angiotensin system, angiogenesis, and extracellular matrix production. We previously reported KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, to activate various gene promoters that are activated in phenotypically modulated smooth muscle cells, such as a nonmuscle type myosin heavy chain gene SMemb, plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1 and VEGF receptors at least in vitro. KLF5/BTEB2 mRNA levels are downregulated with vascular development but upregulated in neointima that is produced in response to vascular injury. Mitogenic stimulation activates KLF5/BTEB2 gene expression through MEK1 and Egr-1. Chromatin immunoprecipitation assay showed KLF5/BTEB2 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation. In order to define the role of KLF5/BTEB2 in cardiovascular remodeling, we targeted the KLF5/BTEB2 gene in mice. Homozygous mice resulted in early embryonic lethality whereas heterozygous mice were apparently normal. However, in response to external stress, arteries of heterozygotes exhibited diminished levels of smooth muscle and adventitial cell activation. Furthermore, cardiac fibrosis and hypertrophy induced by continuous angiotensin II infusion. We also found that RARa binds KLF5/BTEB2, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy. These results indicate that KLF5/BTEB2 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis.

Angiotensin II↗

PubMed2006

Matrix metalloproteinase-2 expression by vascular smooth muscle cells is mediated by both stimulatory and inhibitory signals in response to growth factors.

In response to growth factors, vascular smooth muscle cells (VSMCs) undergo a phenotypic modulation from a contractile, non-proliferative state to an activated, migratory state. This transition is characterized by changes in their gene expression profile, particularly by a significant down-regulation of contractile proteins. Platelet-derived growth factor (PDGF)-BB has long been known to initiate VSMC de-differentiation and mitogenesis. Insulin-like growth factor (IGF)-I, on the other hand, has differing effects depending on the model studied. Here, we report that both IGF-I and PDGF-BB stimulated VSMC de-differentiation of rat heart-derived SMCs in culture, although only PDGF-BB was capable of inducing proliferation. Although both PDGF-BB and IGF-I stimulation resulted in decreased smooth muscle alpha-actin expression and increased matrix metalloproteinase (MMP)-2 expression, the response to IGF-I was significantly more rapid. The increased MMP-2 expression in response to both growth factors was due to increased transcription rates and was dependent on the action of phosphatidylinositol 3-kinase (PI3K) and its downstream effector, Akt. Both PDGF-BB and IGF-I activated PI3K/Akt to similar degrees; however, only PDGF-BB concomitantly stimulated an inhibitory signaling pathway that antagonized the effects of Akt but did not alter the extent or duration of Akt activation. Together, these findings suggest that changes in MMP-2 expression are part of the program of VSMC phenotypic modulation and that both PDGF-BB and IGF-I, despite their different abilities to induce proliferation in this model, are capable of inducing VSMC activation.

Animals↗

PubMed2000

Regulated expression of the BTEB2 transcription factor in vascular smooth muscle cells: analysis of developmental and pathological expression profiles shows implications as a predictive factor for restenosis.

BACKGROUND: We have previously shown BTEB2, a Krüppel-like zinc finger transcription factor, to regulate expression of the SMemb/NMHC-B gene, which has been implicated in phenotypic modulation of smooth muscle cells (SMCs). The present study was done to assess the developmental and pathological expression profiles of BTEB2 and to further evaluate the clinical relevance of BTEB2 expression in human coronary artery disease. METHODS AND RESULTS: Immunohistochemistry showed developmentally regulated expression of BTEB2 with abundant expression in fetal but not in adult aortic SMCs of humans and rabbits. In balloon-injured aortas, predominant expression of BTEB2 was seen in neointimal SMCs. Atherectomy specimens obtained from primary and restenotic lesions showed predominant expression of BTEB2 to stellate SMCs. The incidence of restenosis in primary lesions was significantly higher in lesions containing BTEB2-positive cells than in lesions without (55.6% versus 25.0%, P:=0.01). CONCLUSIONS: The present study shows that BTEB2 expression is developmentally and pathologically regulated. BTEB2 is preferentially expressed in dedifferentiated or activated SMCs. Examination of human coronary artery specimens suggests that primary lesions containing BTEB2-positive cells are associated with higher risk of restenosis than BTEB2-negative lesions. These results suggest that BTEB2 can serve as a molecular marker for phenotypic modulation of vascular SMCs.

Adult↗

PubMed1993

In vivo responses of macrophages and perisinusoidal cells to cholestatic liver injury.

We investigated the response of macrophages and perisinusoidal (Ito) cells (PSCs) during the development of secondary biliary cirrhosis after ligation and division of the common bile duct. Liver tissue was obtained from three groups of male Wistar rats: 1) untreated controls (n = 3); 2) common bile duct-ligated (CBDL) animals (n = 15); and 3) sham-operated controls (n = 15). Material from animal groups 2 and 3 was obtained on days 3, 7, 14, 21, and 28 after operation; in all animals 5-bromo-2-deoxyuridine was administered intraperitoneally before death. Monocytes and macrophages were detected using the monoclonal antibody ED1 and tissue macrophages using the antibody ED2. Cell proliferation within the macrophage population was demonstrated by double labeling for ED2 and incorporated 5-bromo-2-deoxyuridine. PSCs were demonstrated in tissue sections by immunolocalization of desmin; proliferating PSCs were identified by double labeling for desmin and incorporated 5-bromo-2-deoxyuridine. Evidence of phenotypic modulation of PSCs was sought using anti-alpha-smooth muscle actin (alpha-SMA) antibody. Increased numbers of ED1- and ED2-positive cells were seen in CBDL animals at all time points. Local proliferation of macrophages could be identified and reached a peak at day 3, thereafter falling toward control values. Compared with those of controls, livers of CBDL animals showed increased numbers of desmin-positive PSCs in periportal zones from day 3 on, reaching a peak at day 14 (127.8 +/- 10.99 cells/0.635 mm2) and followed by a plateau. PSC proliferation peaked at days 3 and 7 (labeling indices 11.2% and 11.2%, respectively) and thereafter fell toward control values; no expansion of the PSC population was seen in sham-operated rats. Increased alpha-SMA-positive cells were also noted from day 3, with a peak at day 21 (231.1 +/- 11.52 cells/0.635 mm2) and followed by a plateau. En face labeling experiments in days 14, 21, and 28 CBDL animals showed cells co-expressing alpha-SMA and desmin and cells expressing alpha-SMA alone. These results indicate that in response to chronic cholestatic liver injury, PSCs proliferate and undergo phenotypic modulation toward "myofibroblast-like" cells. The kinetics of the response are similar to those of the ED2-positive cell population in keeping with a hypothesis that PSC proliferation and activation may be mediated by factors released by macrophages in response to various forms of liver injury. We conclude that the responses of macrophages and PSCs to cholestatic injury are similar to those after toxin-induced hepatocyte necrosis.

Actins↗

PubMed2000

Cyclic GMP-dependent protein kinase expression in coronary arterial smooth muscle in response to balloon catheter injury.

Arterial smooth muscle cells undergo phenotypic and proliferative changes in response to balloon catheter injury. Nitric oxide (NO) and cGMP have been implicated in the inhibition of vascular smooth muscle cell proliferation and phenotypic modulation in cultured-cell studies. We have examined the expression of the major cGMP receptor protein in smooth muscle, cGMP-dependent protein kinase I (PKG), in response to balloon catheter injury in the swine coronary artery. On injury, there was a transient decrease in the expression of PKG in neointimal smooth muscle cells when compared with medial smooth muscle cells. The decrease in PKG expression was observed in the population of proliferating cells expressing the extracellular matrix protein osteopontin but not in cells present in the uninjured portion of the media. Coincident with the suppression of PKG expression in neointimal cells after injury, there was a marked increase in the expression of type II NO synthase (inducible NOS [iNOS], NOS-II) in the neointimal cells. These results suggest that PKG expression is transiently reduced in response to injury in the population of coronary arterial smooth muscle cells that are actively proliferating and producing extracellular matrix proteins. The reduction in PKG expression is also correlated temporally with increases in inflammatory activity in the injured vessels as assessed by iNOS expression. Coupled with our current knowledge regarding the role of PKG in the regulation of cultured cell phenotypes, these results imply that PKG may also regulate phenotypic modulation of vascular smooth muscle cells in vivo as well.

Angioplasty, Balloon↗

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↗

PubMed1999

Significance of mesangial expression of alpha-smooth muscle actin in the progression of IgA nephropathy.

To determine whether phenotypic modulation of mesangial and interstitial cells correlated with the long-term prognosis of IgA nephropathy (IgAN), we analyzed retrospectively 27 patients with IgAN whose creatinine clearance at the time of renal biopsy was normal. The patients were subdivided into two groups according to the course of renal function during follow-up. Thirteen patients maintained normal renal function for more than 15 years (stable group), and 14 progressed to end-stage renal disease (ESRD group). The score of mesangial cell cellularity in the ESRD group was significantly higher than in the stable group. Immunohistochemistry localized alpha-smooth muscle actin (alpha-SMA) in renal mesangial cells of approximately half these patients. Macrophages localized predominantly in the mesangial area in patients with mesangial expression of alpha-SMA, which was associated with the expression of macrophage-colony-stimulating factor. Noteworthily, the score of mesangial alpha-SMA expression and the incidence of patients with mesangial expression of alpha-SMA at the time of renal biopsy were markedly higher in the ESRD group than in the stable group. However, there was no significant difference in both the score of interstitial alpha-SMA expression and the incidence of patients with interstitial expression of alpha-SMA between these two groups. These results suggest that macrophages recruited into the mesangium may induce phenotypic modulation of mesangial cells and that mesangial alpha-SMA expression predicts a progressive decline in renal function in patients with IgAN.

Actins↗