PubMed Health⌕ Search

Biomedical subjects

M H Stoler

Publications and source records attributed to M H Stoler.

At least 37 records · Page 2Linked to original sources
PubMed2000

Spermatid-specific expression of the novel X-linked gene product SPAN-X localized to the nucleus of human spermatozoa.

Formation of mature spermatozoa involves a series of dramatic molecular and morphological changes in the male germ cell lineage. These changes result from the temporally regulated transcription and translation of several testis-specific gene products. Here, we describe a novel, testis-specific protein designated SPAN-X for sperm protein associated with the nucleus on the X chromosome. SPAN-X sequences showed no significant similarity with known cDNA or peptide sequences. The SPAN-X peptide sequences contained three overlapping consensus nuclear localization signals, a high percentage (33%-37%) of charged amino acid residues, and a relatively acidic isoelectric point (pI; 4.88-6.05). Northern analysis of mRNA from multiple human tissues identified a SPAN-X transcript exclusively in the testis. In situ hybridization of human testes sections showed SPAN-X mRNA expression in haploid, round, and elongating spermatids. The SPANX gene was mapped to chromosome Xq27. 1 by fluorescence in situ hybridization and by Southern blot analysis of human/mouse somatic cell hybrids. On Western blots of human sperm proteins, antirecombinant SPAN-X antibodies reacted with broad bands migrating between 15-20 kDa. Immunofluorescent labeling of human spermatozoa demonstrated SPAN-X localization to nuclear craters and cytoplasmic droplets. Expression of SPAN-X, an X-linked gene product, exclusively in haploid spermatids leads to interesting questions regarding the transcription of sex-linked genes during spermiogenesis.

Amino Acid Sequence↗
PubMed2000

Human papillomaviruses and cervical neoplasia: a model for carcinogenesis.

Human papillomaviruses are etiologic for cervical cancers and their pathologic precursors. As presented in this review, pathologic, epidemiologic, and molecular data all support a working model that accounts for the pathogenetic role of these viruses in cervical neoplasia. Diagnostic criteria and classification systems are discussed in light of this model. These insights point to a potential change in clinical screening systems for cervical cancer. In addition, vaccine trials for oncogenic HPVs have begun. In the long term, these trials may hold promise as truly specific preventive therapy for this common human cancer.

Female↗
PubMed2000

Alveolar epithelial cell chemokine expression triggered by antigen-specific cytolytic CD8(+) T cell recognition.

CD8(+) T lymphocyte responses are a critical arm of the immune response to respiratory virus infection and may play a role in the pathogenesis of interstitial lung disease. We have shown that CD8(+) T cells induce significant lung injury in the absence of virus infection by adoptive transfer into mice with alveolar expression of a viral transgene. The injury is characterized by the parenchymal infiltration of host cells, primarily macrophages, which correlates with physiologic deficits in transgenic animals. CD8(+) T cell-mediated lung injury can occur in the absence of perforin and Fas expression as long as TNF-alpha is available. Here, we show that the effect of TNF-alpha expressed by CD8(+) T cells is mediated not exclusively by cytotoxicity, but also through the activation of alveolar target cells and their expression of inflammatory mediators. CD8(+) T cell recognition of alveolar cells in vitro triggered monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) expression in the targets, which was mediated by TNF-alpha. Antigen-dependent alveolar MCP-1 expression was observed in vivo as early as 3 hours after CD8(+) T cell transfer and depended upon TNF-R1 expression in transgenic recipients. MCP-1 neutralization significantly reduced parenchymal infiltration after T cell transfer. We conclude that alveolar epithelial cells actively participate in the inflammation and lung injury associated with CD8(+) T cell recognition of alveolar antigens.

Animals↗
PubMed2000

Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness.

Estrogen (E) regulates the synthesis and secretion of several pituitary hormones during the reproductive cycle in a cell- and promoter-specific manner. One mechanism underlying cell specificity is the differential expression of estrogen receptor (ER) isoforms. We used in vivo and in vitro rodent pituitary cell models to examine the expression and regulation of ERalpha, ERbeta, and the pituitary-specific ERalpha isoform, truncated estrogen receptor product-1 (TERP-1). In cycling female rat pituitaries, ERbeta messenger RNA (mRNA) levels fell 40% on the morning of proestrus and were suppressed by E or dihydrotestosterone in ovariectomized females. In lactotrope and gonadotrope cell lines (GH3, RC4B, LbetaT2), progesterone (P) or P plus E also suppressed ERbeta. TERP-1 mRNA increased 3-fold at proestrus and in response to E treatment in vivo and in cell lines. ERalpha mRNA levels were not regulated significantly by any treatment in vivo or in cell lines. However, E suppressed ERalpha protein levels in vivo and in cell lines, and reduction of ERalpha protein levels by E or the antiestrogen ICI182,780 reduced E-stimulated transcriptional activation of the PRL promoter in GH3 cells. TERP-1 and ERbeta protein levels were low to undetectable in cell lines, but E stimulated TERP-1. Because E treatment decreases ERbeta mRNA and ERalpha protein and increases levels of TERP-1 (which can suppress ERalpha/beta activity), the dynamic steroid-induced changes in ER expression in the rat pituitary during the midcycle gondaotropin/PRL surge may provide a means for ovarian steroids to limit positive feedback.

Animals↗
PubMed1999

Recurrent Epstein-Barr virus-associated post-transplant lymphoproliferative disorder: report of a patient with histologically similar but clonally distinct metachronous abdominal and brain lesions.

A liver transplant patient developed a single central nervous system (CNS) intraparenchymal lesion 5 months after the diagnosis of an intraabdominal diffuse large B-cell post-transplant lymphoproliferative disorder (PTLD). Biopsy of the new CNS lesion showed a diffuse large B-cell PTLD morphologically and immunohistochemically indistinguishable from the abdominal lesion. In addition, both lesions were positive for Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR) and for EBV-encoded RNA by in situ hybridization. Although these results were consistent with a metastatic origin for the CNS lesion, the finding of an intraparenchymal lesion without leptomeningeal or dural spread was suggestive of a new primary CNS lymphoma. Proof that the brain lesion was a second primary and not a metastasis was obtained by immunoglobulin gene rearrangement studies and assessment of EBV clonality. Multiple primary lymphoid neoplasms arise at higher frequency in the setting of immunosuppression, and molecular investigations of tumor clonality can provide clinically relevant staging and prognostic information.

Abdominal Neoplasms↗
PubMed1999

Detection of the alpha-subunit of inhibin in trophoblastic neoplasia.

Placental trophoblasts are the primary source of serum inhibin during pregnancy. We sought to characterize inhibin immunolabeling in trophoblastic neoplasms and compare the results with those for established markers of trophoblastic differentiation. Formalin-fixed, paraffin-embedded tissues from three normal term placentas, 13 hydatidiform moles (HM), five choriocarcinomas (CC) (three gestational, one testicular, one mediastinal), and five placental site trophoblastic tumors (PSTT) were immunolabeled with antibodies to the alpha-subunit of inhibin, hPL, and beta-hCG. Additionally, six first-trimester placentas were immunolabeled with antibody to inhibin alone. Trophoblastic subpopulations were assessed for the number of positive cells (1% to 24% = 1+,25% to 49% = 2+,50% to 74% = 3+, 75% to 100% = 4+). Immunolabeling in term placenta and HM was similar, because beta-hCG was the most sensitive marker (4+) of syncytiotrophoblasts followed by inhibin (3-4+) and hPL (2-3+). Immunolabeling of syncytiotrophoblasts in CC was similar to that in term placenta and HM, except for negative hPL staining in two cases. In HM, inhibin labeling of intermediate trophoblasts (2-3+) was less than that for hPL (3-4+). In CC, inhibin and hPL labeling of intermediate trophoblasts was more variable with negative hPL reactivity in two cases. Inhibin and hPL did not stain cytotrophoblasts. In PSTT, inhibin immunolabeling was a better marker than hPL in two cases, inferior in two, and similar in one. Inhibin labeling of syncytiotrophoblasts was less than that for beta-hCG, but did not have the often marked background staining that was present with beta-hCG. Immunolabeling of trophoblast subpopulations for inhibin was similar between first-trimester placenta, term placenta, and HM. We conclude that inhibin is a useful immunohistochemical marker of trophoblastic neoplasia and should be included in the antibody panel with beta-hCG and hPL.

Adult↗
PubMed1999

Inhibin is not an immunohistochemical marker for hepatocellular carcinoma. An example of the potential pitfall in diagnostic immunohistochemistry caused by endogenous biotin.

Inhibin is a heterodimeric glycoprotein originally detected in gonadal tissues. One report described inhibin immunopositivity in 17 of 19 hepatocellular carcinomas (HCCs) and the hepatocytes of the surrounding nonneoplastic parenchyma. The reported immunohistochemical method, which used avidin-biotin complex, did not describe blocking endogenous biotin. Since liver tissue may contain high levels of biotin, endogenous biotin may result in false-positive immunostaining. We wondered whether this reported immunopositivity represented a false-positive result due to unblocked endogenous biotin. By using a similar antigen retrieval technique and the same specificity, titer, and clonal source of primary antibody as the aforementioned study, we performed immunostaining for inhibin with and without an endogenous biotin blocking step on 23 cases of HCC and the surrounding cirrhotic liver. In all cases, the HCC and the hepatocytes in the cirrhotic nodules were negative for inhibin when the endogenous biotin blocking step was used. When the blocking step was omitted, apparent immunostaining was noted in 20 of 23 HCCs and in the hepatocytes in all cases. Accordingly, HCC and the hepatocytes of the surrounding cirrhotic liver are immunohistochemically negative for inhibin. The previously reported immunopositivity of HCC and nontumoral hepatocytes for inhibin represents a false-positive result due to endogenous biotin.

Biomarkers↗
PubMed1999

Detection of multiple human papillomavirus types in Condylomata acuminata lesions from otherwise healthy and immunosuppressed patients.

Condylomata acuminata, or genital warts, are proliferative lesions of genital epithelium caused by human papillomavirus (HPV) infection. HPV types 6 and 11 are most often detected in these lesions. Genital lesions consistent with exophytic condylomata acuminata were removed by excision biopsy from 65 patients, 41 of whom were otherwise healthy individuals (control group) and 24 of whom had conditions known to cause immunosuppression. Histologically, the majority of the lesions were typical condylomata acuminata. Three lesions removed from immunosuppressed individuals also contained foci of moderate to severe dysplasia (intraepithelial neoplasia grade II/III). A recently developed PCR and reverse blot strip assay was used to determine the specific HPV types present in the genital lesions. With a set of oligonucleotide primers based on the same primer binding regions used for the MY09 and MY11 primer pair, this PCR assay detects the presence of 27 HPV types known to infect the genital tract. All but two condylomata acuminata contained either HPV type 6 or 11. The predominant type in the lesions from control patients was HPV 6, while lesions from immunosuppressed types most often contained HPV 11. Condylomata acuminata from immunosuppressed patients contained significantly more overall HPV types than lesions from the control group. HPV types associated with an increased risk of dysplasia (high-risk types) were detected in 42 (64.6%) of the total of 65 specimens; 18 (43.9%) specimens were detected in the 41 otherwise healthy individuals, and 24 (100%) specimens were detected in the 24 immunosuppressed patients. HPV 16 was the most common high-risk type detected, found in 21 of 65 (32.3%) specimens. After HPV types 6 and 11, HPV types 53 and 54 were the most frequently detected low-risk HPV types. This study demonstrates that a high percentage of condylomata acuminata lesions contain multiple HPV types, including types associated with a high risk of dysplastic abnormalities. Further studies are needed to determine the influence these additional HPV types have on the epidemiology of genital tract HPV infections and the natural history of condylomata acuminata, especially in immunosuppressed patients.

Adolescent↗
PubMed1998

Structural and functional consequences of alveolar cell recognition by CD8(+) T lymphocytes in experimental lung disease.

CD8(+) T cells infiltrate the lung in many clinical conditions, particularly in interstitial lung disease. The role(s) that CD8(+) T cells might be playing in the pathogenesis of inflammatory lung disease is unclear at present, as is the direct contribution of CD8(+) T cell effector activities to lung injury. This report describes a transgenic model used to evaluate the impact, on respiratory structure and function, of CD8(+) T lymphocyte recognition of a target antigen expressed endogenously in alveolar epithelial cells. We found that adoptive transfer of cloned CD8(+) cytotoxic T lymphocytes (CTLs) specific for an alveolar neo-antigen (influenza hemagglutinin) leads to progressive lethal injury in transgenic mice, which dramatically affects lung structure and function. Transgenic recipients of CD8(+) CTLs exhibited tachypnea and progressive weight loss, becoming moribund over a period of several days. Concomitantly, the animals developed a progressive interstitial pneumonitis characterized initially by lymphocytic infiltration of alveolar walls and spaces, followed by an exuberant mononuclear cell infiltration that correlated with restrictive pulmonary mechanics and a progressive diffusion impairment. These results indicate that antigen-specific CD8(+) T cell recognition of an alveolar epithelial "autoantigen" is, in and of itself, sufficient to trigger an inflammatory cascade that results in the histological and physiological manifestations of interstitial pneumonia.

Adoptive Transfer↗
PubMed1998

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1alpha.

Interleukin-1alpha (IL-1alpha) is a multifunctional cytokine that promotes inflammation, tissue remodeling and epithelial hyperplasia. Keratinocytes produce and sequester large amounts of biologically active IL-1alpha which can be released after injury or infection. We show that high level expression of human papillomavirus (HPV) type 16 E6 and E7 oncoproteins enhanced release of IL-1alpha from cultures of normal cervical keratinocytes (relative effectiveness E7 > E6/E7 >> E6 > control). The amount of IL-1alpha released was directly related to the ability of E7 or E6/E7 to stimulate apoptosis. E7 proteins that bound the retinoblastoma protein (Rb) strongly (HPV-16 and -18) induced more IL-1alpha release than those that bound poorly (HPV-6 and an HPV-16 E7 24gly mutant). Furthermore, overexpression of the E2F-1 transcription factor, a downstream target of Rb, induced extensive apoptosis and IL-1alpha release. Apoptosis and IL-1alpha release in response to growth factor removal occurred in part through a p53-independent pathway as coexpression of E6 and downregulation of p53 did not prevent either response. Immunohistochemical analyses showed that IL-1alpha was expressed by keratinocytes in normal cervical epithelia, low and high grade dysplasias, and cervical carcinomas. However, HPV-16 E6/E7 RNA expression and apoptosis increased in parallel in proliferating keratinocytes in severe dysplasias and carcinomas suggesting that IL-1alpha release is associated with progression to high grade disease. Thus, high level expression of the HPV-16 E7 protein sensitizes keratinocytes to apoptosis which results in release of IL-1alpha.

Apoptosis↗
PubMed1998

Interobserver variability in the classification of proliferative breast lesions by fine-needle aspiration: results of the Papanicolaou Society of Cytopathology Study.

This study evaluates the applicability of the published cytologic criteria in the categorization of proliferative breast lesions by assessing the diagnostic accuracy and interobserver reproducibility of a panel of experts. Twelve breast fine-needle aspiration (FNA) specimens of biopsy-proven nonproliferative breast lesion (NPL) (1 case), proliferative lesions without atypia (PL) (7 cases), proliferative lesion with atypia (PLA) (1 case), and low-nuclear grade ductal carcinoma in situ (DCIS) (3 cases) were selected. Six FNAs were Papanicolaou (PAP) and 6 were Diff-Quik-stained (DQ). Six expert cytopathologists classified the smears using a summary of published criteria as a guideline. All 6 participants rendered the same cytologic diagnosis in 2/12 (16%) cases. The agreement among the 6 raters was low (Kappa = 0.35). Cytohistologic correlation was achieved in 26/72 (36%) FNA diagnoses. The correlation of the PAP-stained cases was better than the DQ: 17/36 (47%) PAP and 9/36 (25%) DQ correlated. Improving the correlation was achieved by amalgamation of NPL and PL into "low risk" and PLA and DCIS into "high risk" categories: 47/72 (65%) FNA diagnoses then correlated with histology [29/36 (81%) PAP and 18/36 (50%) DQ]. We conclude that the cytologic criteria of proliferative breast lesions need to be further defined and assessed. Consideration should be given to minimizing the number of diagnostic categories and adopting a terminology that has a direct effect on patient management.

Adult↗
PubMed1998

Atypical glandular cells of undetermined significance: a five-year retrospective histopathologic study.

OBJECTIVE: Our purpose was to ascertain the types and frequency of pathologic conditions associated with atypical glandular cells of undetermined significance on Papanicolaou smears. STUDY DESIGN: A 5-year retrospective review of screening cervical cytologic examinations diagnosed as atypical glandular cells of undetermined significance was performed at the University of Virginia to determine pathologic findings associated with atypical glandular cells of undetermined significance on Papanicolaou smears stratified by subtype and overall. RESULTS: Pathologic findings for the respective Papanicolaou smears with the diagnosis of atypical glandular cells of undetermined significance not otherwise specified, favor benign, squamous intraepithelial lesions, and favor neoplasia through the follow-up interval were as follows: squamous intraepithelial lesions in 11%, 8%, 38%, and 20%; adenocarcinoma in situ in 3%, 0%, 0%, and 10%; endometrial hyperplasia in 3%, 5%, 1%, and 2%; and cancer in 8%, 3%, 1%, and 7%. Overall, 63 patients (32%) had preinvasive or invasive lesions. CONCLUSIONS: Atypical glandular cells of undetermined significance on Papanicolaou smears were correlated with significant findings in 45% of patients (32% with preinvasive or invasive lesions and 13% with benign lesions). A prompt and aggressive workup is recommended.

Adolescent↗
PubMed1998

Sebaceous carcinoma. Tumor progression through mutational inactivation of p53.

BACKGROUND: Sebaceous carcinoma may masquerade for years as an inflammatory condition. In many cases, this may be because of the presence of longstanding intraepithelial disease (e.g., dysplasia or carcinoma in situ), which eventually progresses to invasive carcinoma recognized through tumefaction and a worsening clinical presentation. The mechanism for this tumor progression is unknown. In the Far East, human papilloma virus (HPV) has been suggested to play a role in the development of sebaceous carcinoma by inactivating tumor suppressor gene p53. Here, the authors explore the molecular basis of the progression of ocular sebaceous carcinoma. METHODS: Cases of sebaceous carcinoma seen at the University of Virginia, Department of Ophthalmology, during the period from 1989 to 1996 were analyzed for HPV infection by in situ hybridization and polymerase chain reaction. The expression of p53, p21WAF-1, Bcl-2, and epithelial membrane antigen was examined by immunohistochemistry. In one of the cases, frozen tumor was available, allowing exons 5 through 9 of the p53 gene to be sequenced. RESULTS: Seven cases were identified, all of which were from women. All were negative for HPV. In cases in which disease was restricted to dysplasia (carcinoma in situ), p53 but not p21WAF-1 was negative. In contrast, cases that contained a component of invasive or metastatic carcinoma showed striking hyperexpression of nuclear p53 in all of the malignant cells. In one of these cases, a G:C-->T:A transversion was found in the p53 gene. This mutation, characteristic of bulky carcinogens, substituted phenylalanine for cysteine 277, a residue that participates in hydrogen bonding to the p53 DNA binding consensus sequence. CONCLUSIONS: Mutational inactivation of p53 may be involved in the progression of sebaceous carcinoma.

Adult↗
PubMed1998

Cutaneous verruciform xanthoma: a report of five cases investigating the etiology and nature of xanthomatous cells.

Verruciform xanthoma is a rare clinicopathologic entity of uncertain etiology that occurs primarily in the oral mucosa. Aggregates of foam cells in the submucosal stroma or papillary dermis in association with verrucous epithelial hyperplasia are the hallmark of this lesion. Extraoral (cutaneous) occurrence of verruciform xanthoma is much rarer and has been reported mostly in the genital skin. Five cases of extraoral cutaneous verruciform xanthoma (three from the scrotum, one from the penis, and one from the nose) and one histologic "simulant" (from skin of the nose) were studied. The lesions were solitary, raised, or polypoid with cup-shaped craters filled with parakeratotic cells that blended into keratinocytes of an acanthotic and papillomatous epidermis. There was a neutrophilic infiltrate of varying intensity between plump parakeratotic cells and keratinocytes, near the surface of the epidermis. Aggregates of foam cells were present in the papillary dermis, which was highly vascular. A plasma cell predominant infiltrate was seen at the base in a bandlike fashion. Despite the architectural resemblance of verruciform xanthoma to verrucous mucocutaneous lesions related to human papillomavirus infection, it was not detected by either immunohistochemistry, in situ hybridization, polymerase chain reaction, or Southern blot analysis in any case. The foam cells were weakly positive for cytokeratin and for Factor XIIIa but negative for S-100 protein. The KP1 and Mac 387 immunostain showed focal weak staining in foam cells. We postulate that a cascade of events pursue after initial keratinocytic damage attracting neutrophils, with subsequent phagocytosis of necrotic keratinocytic debris by dermal dendrocytes, eventually leading to the ultimate manifestation of the lesion as verruciform xanthoma. The etiologic agent remains elusive, but based on our findings, we conclude that verruciform xanthoma is most likely not a human papillomavirus-associated squamoproliferative lesion and that the foam cells, a histologic hallmark of the lesion, are most likely derived from dermal dendritic cells.

Adult↗
PubMed1998

The diagnostic utility of inhibin staining in ovarian neoplasms.

Previous immunohistologic studies have suggested that the antibody to the alpha subunit of inhibin is a sensitive marker of sex cord-stromal differentiation. However, detection has also been reported within both ovarian epithelial and germ cell tumors. To further study the normal tissue distribution of inhibin and the utility of its detection for the differential diagnosis of ovarian sex cord-stromal neoplasms, normal tissues and 225 lesions including sex cord-stromal lesions, ovarian epithelial and stromal cancers, ovarian and testicular germ cell tumors, metastases to the ovary, and non-ovarian cancers were analyzed using semi-automated immunohistochemistry. In normal tissues, immunostaining was found in cell subsets of the ovary, testis, adrenal gland, placenta, and kidney. All sex cord-stromal tumors were inhibin-positive and 37 of 50 (74%) cases exhibited at least moderate to strong immunostaining. Two cases originally diagnosed as adult granulosa cell tumors that were inhibin-negative were reassessed; diagnoses of endometrioid stromal sarcoma and endometrioid carcinoma with sertoliform features were rendered. In other primary or metastatic ovarian lesions or metastases to the ovary, weak to moderate immunostaining was found in only 4 of 84 (4.8%) cases, including ovarian clear cell carcinoma (2/2), uterine clear cell carcinomas metastatic to the ovary (1/3), and serous papillary carcinoma (1/2). Similarly, only 4 of 66 (6.1%) non-ovarian neoplasms exhibited weak immunostaining, including melanoma (1/5), uterine endometrioid carcinoma (1/2), transitional cell carcinoma (1/3), and breast adenocarcinoma (1/8). Only one case of a non-sex cord-stromal tumor had moderate or strong immunostaining. Based on these results, immunohistologic detection of the alpha subunit of inhibin is a useful adjunct in the differential diagnosis of sex cord-stromal neoplasms.

Adult↗
PubMed1998

Papillary squamotransitional cell carcinoma of the vagina.

A case of papillary squamotransitional carcinoma of the vagina is reported. The immunohistochemical profiles (cytokeratin-7 and -20) and the detection of human papillomavirus 16 support its close relationship to conventional squamous cell carcinoma. The lesion is compared to previously reported cases of papillary transitional cell carcinoma of the vagina and papillary squamotransitional cell carcinoma of the cervix.

Aged↗
PubMed1998

Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1.

Type II nitric oxide synthase (NOS) is upregulated in the pulmonary vasculature in a chronic hypoxia model of pulmonary hypertension. In situ hybridization analysis demonstrates that type II NOS RNA is increased in the endothelium as well as in the vascular smooth muscle in the lung. The current studies examine the role of hypoxia-inducible factor (HIF)-1 in regulating type II NOS gene expression in response to hypoxia in pulmonary artery endothelial cells. Northern blot analyses demonstrate a two fold increase in HIF-1 alpha but not in HIF-1 beta RNA with hypoxia in vivo and in vitro. Electrophoretic mobility shift assays show the induction of specific DNA binding activity when endothelial cells were subjected to hypoxia. This DNA binding complex was identified as HIF-1 using antibodies directed against HIF-1 alpha and HIF-1 beta. Transient transfection of endothelial cells resulted in a 2.7-fold increase in type II NOS promoter activity in response to hypoxia compared with nonhypoxic controls. Mutation or deletion of the HIF-1 site eliminated the response to hypoxia. These results demonstrate that HIF-1 is essential for the hypoxic regulation of type II NOS gene transcription in pulmonary endothelium.

Animals↗