J. Gordon Porter
Incyte
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Featured researches published by J. Gordon Porter.
Journal of Clinical Investigation | 1999
Richard M. Lawn; David Wade; Michael Garvin; Xingbo Wang; Karen Schwartz; J. Gordon Porter; Jeffrey J. Seilhamer; Ashley M. Vaughan; John F. Oram
The ABC1 transporter was identified as the defect in Tangier disease by a combined strategy of gene expression microarray analysis, genetic mapping, and biochemical studies. Patients with Tangier disease have a defect in cellular cholesterol removal, which results in near zero plasma levels of HDL and in massive tissue deposition of cholesteryl esters. Blocking the expression or activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured cells, and increasing expression of ABC1 enhances it. ABC1 expression is induced by cholesterol loading and cAMP treatment and is reduced upon subsequent cholesterol removal by apolipoproteins. The protein is incorporated into the plasma membrane in proportion to its level of expression. Different mutations were detected in the ABC1 gene of 3 unrelated patients. Thus, ABC1 has the properties of a key protein in the cellular lipid removal pathway, as emphasized by the consequences of its defect in patients with Tangier disease.
Circulation Research | 2004
Blanche Schroen; Stephane Heymans; Umesh Sharma; W. Matthijs Blankesteijn; Saraswati Pokharel; Jack P.M. Cleutjens; J. Gordon Porter; Chris T. Evelo; Rudy F. Duisters; Rick van Leeuwen; Ben J. A. Janssen; Jacques Debets; Jos F.M. Smits; Mat J.A.P. Daemen; Harry J.G.M. Crijns; Paul Bornstein; Yigal M. Pinto
Cardiac hypertrophy can lead to heart failure (HF), but it is unpredictable which hypertrophied myocardium will progress to HF. We surmised that apart from hypertrophy-related genes, failure-related genes are expressed before the onset of failure, permitting molecular prediction of HF. Hearts from hypertensive homozygous renin-overexpressing (Ren-2) rats that had progressed to early HF were compared by microarray analysis to Ren-2 rats that had remained compensated. To identify which HF-related genes preceded failure, cardiac biopsy specimens were taken during compensated hypertrophy and we then monitored whether the rat progressed to HF or remained compensated. Among 48 genes overexpressed in failing hearts, we focused on thrombospondin-2 (TSP2). TSP2 was selectively overexpressed only in biopsy specimens from rats that later progressed to HF. Moreover, expression of TSP2 was increased in human hypertrophied hearts with decreased (0.19±0.01) versus normal ejection fraction (0.11±0.03 [arbitrary units]; P<0.05). Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice. In TSP2 knockout mice, angiotensin II increased matrix metalloproteinase (MMP)-2 and MMP-9 activity by 120% and 390% compared with wild-type mice (P<0.05). In conclusion, we identify TSP2 as a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading and that may function by its regulation of MMP activity. This suggests that expression of TSP2 marks an early-stage molecular program that is activated uniquely in hypertrophied hearts that are prone to fail.
Biochemical and Biophysical Research Communications | 1989
Jeffrey J. Seilhamer; Ann E. Arfsten; Judy Miller; Penny Lundquist; Robert M. Scarborough; John A. Lewicki; J. Gordon Porter
A cDNA clone encoding porcine brain natriuretic peptide (BNP) precursor was used to probe a canine genomic DNA library for homologous sequences. A unique clone was obtained (D1) which encoded a peptide homologous to porcine BNP. A 4.0 kB Hind III fragment of D1 containing the entire BNP precursor coding region was hybridized against blots of EcoRI digested human genomic DNA. A 7.0 kB hybridizing band was observed, which was subsequently subcloned and sequenced. This human clone, H1, also contained a sequence homologous to porcine BNP precursor. Transcription of the human BNP gene was confirmed by detection of BNP-specific sequences amplified from human atrial RNA by polymerase chain reaction. These results suggest that both BNP and ANP are present and function in a wide variety of mammalian species.
Biochemical and Biophysical Research Communications | 1990
J. Gordon Porter; Ann E. Arfsten; Forrest Fuller; Judith A. Miller; Lisa C. Gregory; John A. Lewicki
The amino acid sequence of the human atrial natriuretic peptide clearance receptor (ANP C-receptor) was deduced from the nucleotide sequence of cDNA clones obtained from human placental and kidney cDNA libraries. The human sequence is highly homologous to the bovine C-receptor sequence already described, and the corresponding mRNA is expressed in human placenta, adult and fetal kidney and fetal heart. Upon transfection of this cDNA into mammalian cells, recombinant expression experiments revealed that the human ANP C-receptor has a high affinity for ANP (6 x 10(-9) M), similar to that observed for the receptor in other species. These data indicate that the human ANP C-receptor, previously characterized in other mammalian species, is highly conserved structurally and is expressed in various human tissues.
Circulation | 2005
Esther Lutgens; Birgit C.G. Faber; Kitty Schapira; Chris T. Evelo; Rachel I. M. van Haaften; Sylvia Heeneman; Kitty B. J. M. Cleutjens; Ann Pascale Bijnens; Linda Beckers; J. Gordon Porter; Charles R. Mackay; Paul D. Rennert; Veronique Bailly; Matthew Jarpe; Brian M. Dolinski; Victor Koteliansky; Tony de Fougerolles; Mat J.A.P. Daemen
Background—Pathological aspects of atherosclerosis are well described, but gene profiles during atherosclerotic plaque progression are largely unidentified. Methods and Results—Microarray analysis was performed on mRNA of aortic arches of ApoE−/− mice fed normal chow (NC group) or Western-type diet (WD group) for 3, 4.5, and 6 months. Of 10 176 reporters, 387 were differentially (>2×) expressed in at least 1 group compared with a common reference (ApoE−/−, 3- month NC group). The number of differentially expressed genes increased during plaque progression. Time-related expression clustering and functional grouping of differentially expressed genes suggested important functions for genes involved in inflammation (especially the small inducible cytokines monocyte chemoattractant protein [MCP]-1, MCP-5, macrophage inflammatory protein [MIP]-1&agr;, MIP-1&bgr;, MIP-2, and fractalkine) and matrix degradation (cathepsin-S, matrix metalloproteinase-2/12). Validation experiments focused on the gene cluster of small inducible cytokines. Real-time polymerase chain reaction revealed a plaque progression–dependent increase in mRNA levels of MCP-1, MCP-5, MIP-1&agr;, and MIP-1&bgr;. ELISA for MCP-1 and MCP-5 showed similar results. Immunohistochemistry for MCP-1, MCP-5, and MIP-1&agr; located their expression to plaque macrophages. An inhibiting antibody for MCP-1 and MCP-5 (11K2) was designed and administered to ApoE−/− mice for 12 weeks starting at the age of 5 or 17 weeks. 11K2 treatment reduced plaque area and macrophage and CD45+ cell content and increased collagen content, thereby inducing a stable plaque phenotype. Conclusions—Gene profiling of atherosclerotic plaque progression in ApoE−/− mice revealed upregulation of the gene cluster of small inducible cytokines. Further expression and in vivo validation studies showed that this gene cluster mediates plaque progression and stability.
Current Opinion in Biotechnology | 2000
Dov Shiffman; J. Gordon Porter
Recent development of gene expression profiling technologies has enabled the large-scale analysis of gene expression changes during disease progression. Frequently, cardiovascular diseases involve complex interactions of multiple cell types over prolonged periods of time. A better understanding of the pathology of cardiovascular diseases and the potential identification of underlying genetic defects are currently being explored by using profiling methodologies in a number of animal and tissue-culture models.
Archive | 1991
J. Gordon Porter; Forrest Fuller; Judith A. Miller; Lisa C. Gregory; John A. Lewicki
The atrial natriuretic peptides (ANP) elicit numerous biological effects by interacting with multiple ANP receptors. At least three receptors have been characterized. The ANP A-receptor, and a related receptor, the ANP B-receptor, contain an ANP binding domain and guanylate cyclase catalytic activity in a single polypeptide chain. These receptors promote increases in intracellular cyclic guanosine monophosphate (GMP) which then mediate many of the direct biological actions of the atrial natriuretic peptides. A third receptor, the ANP C-receptor, is not a guanylate cyclase. Rather, this receptor mediates the sequestration and metabolic clearance of ANP from the circulation. A cDNA encoding the human ANP C-receptor was cloned from a human kidney cDNA library. The deduced amino acid sequence is 95% identical to that of the bovine ANP C-receptor. In addition, the extracellular binding domain of the human ANP C-receptor is 33% identical with the human ANP A-receptor. The localization of ANP C-receptor mRNA in human adult and fetal kidney and fetal heart provides further evidence that this receptor is operative in mediating the metabolic clearance of NP in man.
Journal of Hypertension | 1994
Jeffrey J. Seilhamer; John A. Lewicki; Robert M. Scarborough; J. Gordon Porter
Journal of Biological Chemistry | 2000
Dov Shiffman; Thomas Mikita; Julie T. N. Tai; David Wade; J. Gordon Porter; Jeffrey J. Seilhamer; Roland Somogyi; Shoudan Liang; Richard M. Lawn
Molecular Endocrinology | 2007
Marie-Louise Ricketts; Mark V. Boekschoten; Arja J. Kreeft; Guido Hooiveld; C.J.A. Moen; Michael Müller; Rune R. Frants; Soemini Kasanmoentalib; Sabine M. Post; J. Gordon Porter; Martijn B. Katan; Marten H. Hofker; David D. Moore