Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth.
*Collateral Circulation/drug effects; *Coronary Circulation/drug effects; *MAP Kinase Signaling System/drug effects; Acetophenones/pharmacology; Animal; Animals; Blood Flow Velocity; Cells; Coronary Vessels/surgery; Cultured; Disease Models; Ditiocarb/pharmacology; Endothelial Cells/drug effects/enzymology/*metabolism; Enzyme Inhibitors/pharmacology; Humans; Imidazoles/pharmacology; Inbred WKY; Ligation; Male; Myocardial Reperfusion Injury/enzymology/metabolism/*physiopathology; NADPH Oxidases/antagonists & inhibitors/metabolism; Neovascularization; Onium Compounds/pharmacology; Oxygenases/antagonists & inhibitors/metabolism; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism; Physiologic; Pyridines/pharmacology; Rats; Reactive Oxygen Species/*metabolism; Superoxide Dismutase/antagonists & inhibitors/metabolism; Vascular Endothelial Growth Factor A/metabolism
Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 +/- 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 +/- 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 +/- 4% of normal zone). Similar results were obtained with apocynin following RI (32 +/- 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 +/- 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 +/- 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.
Rocic Petra; Kolz Christopher; Reed Ryan; Potter Barry; Chilian William M
American journal of physiology. Heart and circulatory physiology
2007
2007-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.01330.2006" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.01330.2006</a>
Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction.
alpha Subunit/metabolism; Amino Acids; Animal; Animals; Apoptosis/drug effects; Cardiotonic Agents/*pharmacology; Cell Hypoxia; Cell Line; CXCR4/deficiency/genetics/*metabolism; Dicarboxylic/*pharmacology; Disease Models; Enzyme Inhibitors/pharmacology; hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors/metabolism; Inbred C57BL; Knockout; Left/*drug effects; Mice; myocardial infarction; Myocardial Infarction/*drug therapy/genetics/metabolism/pathology/physiopathology; Myocardium/*metabolism/pathology; Rats; Receptors; Recovery of Function; Signal Transduction/drug effects; stem cells; Stem Cells/drug effects/metabolism; Stroke Volume/drug effects; Time Factors; Up-Regulation; Ventricular Function
The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased
Mayorga Mari; Kiedrowski Matthew; Shamhart Patricia; Forudi Farhad; Weber Kristal; Chilian William M; Penn Marc S; Dong Feng
American journal of physiology. Heart and circulatory physiology
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00449.2015" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00449.2015</a>
Sexual dimorphism in prostanoid-potentiated vascular contraction: roles of endothelium and ovarian steroids.
*Sex Characteristics; Animals; Aorta/drug effects/physiology; Bridged Bicyclo Compounds; Cyclooxygenase Inhibitors/pharmacology; Endothelium; Enzyme Inhibitors/pharmacology; Estrogens/*physiology; Fatty Acids; Female; Heterocyclic; Hydrazines/pharmacology; Imidazoles/pharmacology; Indomethacin/pharmacology; Male; Ovariectomy; Phenylephrine/pharmacology; Progesterone/*physiology; Prostaglandins/*metabolism; Rats; Sprague-Dawley; Thromboxanes/metabolism; Unsaturated; Vascular/*metabolism; Vasoconstriction/drug effects/*physiology; Vasoconstrictor Agents/pharmacology; Vasopressins/pharmacology
The effects of constrictor prostanoid (CP) pathway inhibitors on vascular reactivity to vasopressin (VP) and phenylephrine (PE) were examined in thoracic aortas of male, female, and ovariectomized (OVX) female Sprague-Dawley rats. Maximal contractile response of control (Cont) aortas to VP was markedly higher in females (3,885 +/- 332 mg/mg ring wt) than in males (810 +/- 148 mg). Indomethacin (Indo; 10 microM) attenuated maximal response to VP in females (3,043 +/- 277 mg) but not in males. SQ-29,548 (SQ; 1 microM) attenuated maximal response to VP in females (3,042 +/- 290 mg) to a similar extent as Indo. Dazoxiben (Daz; 10 microM) alone had no effect, but Daz + SQ attenuated maximal contractile response to VP to a similar extent as SQ alone. Removal of the endothelium in female aortas attenuated contractile responses to VP in Cont aortas. OVX attenuated maximal contractile response to VP in Cont aortas (2,093 +/- 329 mg) and abolished the attenuating effects of Indo. Indo, SQ, and Daz exerted identical effects on contractile responses of male, female, and OVX female aortas to PE. These findings establish the following in the rat aorta: 1) CP, probably thromboxane and/or endoperoxide, is responsible for approximately
Fulton Clifford T; Stallone John N
American journal of physiology. Heart and circulatory physiology
2002
2002-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00099.2002" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00099.2002</a>
Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels.
13-dienoic Acid/pharmacology; 15-Hydroxy-11 alpha; 9 alpha-(epoxymethano)prosta-5; Anilides/pharmacology; Animals; Capsaicin/analogs & derivatives/pharmacology; Cinnamates/pharmacology; Coronary Vessels/drug effects/*metabolism/physiopathology; Diabetes Mellitus; Diabetic Cardiomyopathies/drug therapy/*metabolism; Enzyme Inhibitors/pharmacology; Inbred C57BL; Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors/*metabolism; Male; Mice; Microvessels/drug effects/physiopathology; NG-Nitroarginine Methyl Ester/pharmacology; Nitric Oxide/*metabolism; Peptides/pharmacology; TRPV Cation Channels/agonists/antagonists & inhibitors/biosynthesis/*metabolism; Type 2/drug therapy/*metabolism; Vasoconstrictor Agents/pharmacology; Vasodilation/drug effects
We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1((-/-))], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 mug.kg(-1).min(-1)) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1((-/-)) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4-6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1((-/-)) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.
Guarini Giacinta; Ohanyan Vahagn A; Kmetz John G; DelloStritto Daniel J; Thoppil Roslin J; Thodeti Charles K; Meszaros J Gary; Damron Derek S; Bratz Ian N
American journal of physiology. Heart and circulatory physiology
2012
2012-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00011.2012" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00011.2012</a>
Cytokine regulation of human sterol 12alpha-hydroxylase (CYP8B1) gene.
Cell Line; Chenodeoxycholic Acid/pharmacology; Chromosome Mapping; DNA-Binding Proteins/genetics/metabolism; Enzyme Inhibitors/pharmacology; Gene Expression Regulation/*drug effects; Genetic/drug effects; Genetic/physiology; Hepatocyte Nuclear Factor 4; Hepatocytes/metabolism; Humans; Interleukin-1/*pharmacology; MAP Kinase Signaling System/drug effects/physiology; Messenger/antagonists & inhibitors; Mitogen-Activated Protein Kinase 8/metabolism; Mitogen-Activated Protein Kinases/antagonists & inhibitors; Phosphoproteins/genetics/metabolism; Phosphorylation; Promoter Regions; Response Elements/genetics; RNA; Steroid 12-alpha-Hydroxylase/antagonists & inhibitors/*genetics; Transcription; Transcription Factors/genetics/metabolism
Sterol 12alpha-hydroxylase (CYP8B1) catalyzes cholic acid synthesis in the liver and is feedback inhibited by bile acids. In addition to activating farnesoid X receptor (nuclear receptor subfamily 1H4), bile acids also induce inflammatory cytokines in hepatocytes. The objective of this study was to investigate the mechanism by which inflammatory cytokines inhibit human CYP8B1 gene transcription. Real-time PCR assays revealed that both chenodeoxycholic acid (CDCA) and interleukin-1beta (IL-1beta) markedly reduced CYP8B1, cholesterol 7alpha-hydroxylase CYP7A1 and hepatic nuclear factor 4alpha (HNF4alpha) mRNA expression levels in human primary hepatocytes. However, CDCA induced, but
Jahan Asmeen; Chiang John Y L
American journal of physiology. Gastrointestinal and liver physiology
2005
2005-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpgi.00207.2004" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00207.2004</a>
Bcl-2 positively regulates Sox9-dependent chondrocyte gene expression by suppressing the MEK-ERK1/2 signaling pathway.
*Gene Expression Regulation; Adenoviridae/genetics; Animals; Apoptosis; beta-Galactosidase/metabolism; Blotting; Butadienes/pharmacology; Caspase Inhibitors; Cell Differentiation; Cell Line; Chondrocytes/*metabolism; Collagen Type II/metabolism; Down-Regulation; Enzyme Inhibitors/pharmacology; Fibroblasts/metabolism; Fluorescence; Genetic; High Mobility Group Proteins/*metabolism; Lac Operon; Luciferases/metabolism; MAP Kinase Kinase Kinases/*metabolism; Messenger/metabolism; Microscopy; Mitogen-Activated Protein Kinase 1/*metabolism; Mitogen-Activated Protein Kinase 3/*metabolism; NF-kappa B/metabolism; Nitriles/pharmacology; Phenotype; Phosphorylation; Promoter Regions; Protein Kinase C-alpha; Protein Kinase C/antagonists & inhibitors; Proteoglycans/metabolism; Proto-Oncogene Proteins c-bcl-2/*metabolism; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Small Interfering/metabolism; SOX9 Transcription Factor; Sprague-Dawley; Time Factors; Transcription; Transcription Factors/*metabolism; Transfection; Western
Bcl-2 is an anti-apoptotic protein that has recently been shown to regulate other cellular functions. We previously reported that Bcl-2 regulates chondrocyte matrix gene expression, independent of its anti-apoptotic function. Here, we further investigate this novel function of Bcl-2 and examine three intracellular signaling pathways likely to be associated with this function. The present study demonstrates that the activity of Sox9, a master transcription factor that regulates the gene expression of chondrocyte matrix proteins, is suppressed by Bcl-2 small interference RNA in the presence of caspase inhibitors. This effect was attenuated by prior exposure of chondrocytes to an adenoviral vector expressing sense Bcl-2. In addition, the down-regulation of Bcl-2, Sox9, and chondrocyte-specific gene expression by serum withdrawal in primary chondrocytes was reversed by expressing Bcl-2. Inhibition of the protein kinase C alpha and NFkappaB pathways had no effect on the maintenance of Sox9-dependent gene expression by Bcl-2. In contrast, whereas the MEK-ERK1/2 pathway negatively regulated the differentiated phenotype in wild type chondrocytes, inhibition of this pathway reversed the loss of differentiation markers and fibroblastic phenotype in Bcl-2-deficient chondrocytes. In conclusion, the present study identifies a specific signaling pathway, namely, MEK-ERK1/2, that is downstream of Bcl-2 in the regulation of Sox9-dependent chondrocyte gene expression and phenotype.
Yagi Rieko; McBurney Denise; Horton Walter E Jr
The Journal of biological chemistry
2005
2005-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M502751200" target="_blank" rel="noreferrer noopener">10.1074/jbc.M502751200</a>
A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene.
Bile Acids and Salts/metabolism; Carcinoma; Cell Line; Cells; Cholesterol 7-alpha-Hydroxylase/*genetics/*metabolism; Cultured; Enzyme Inhibitors/pharmacology; Genetic/drug effects/*physiology; Hepatocellular/*metabolism/pathology; Hepatocyte Nuclear Factor 4/metabolism; Hepatocytes/drug effects/*metabolism/pathology; Humans; Hydroxamic Acids/pharmacology; Liver Neoplasms/*metabolism/pathology; Messenger/metabolism; RNA; Signal Transduction/physiology; Smad3 Protein/metabolism; Transcription; Transforming Growth Factor beta1/*metabolism; Tumor
BACKGROUND & AIMS: Inhibition of cholesterol 7alpha-hydroxylase (CYP7A1) by bile acids and inflammatory cytokines provides an important mechanism to protect hepatocytes from bile acid toxicity during cholestasis. Transforming growth factor beta1 (TGFbeta1) released by hepatic stellate cells during chronic liver injury plays a critical role in liver inflammation and fibrogenesis. The objective of this study is to investigate the role of TGFbeta1 in hepatic bile acid synthesis. METHODS: mRNA expressions in primary human hepatocytes and HepG2 cells were measured by quantitative real-time polymerase chain reaction. Reporter assay, glutathione-S-transferase pull-down assay, adenovirus-mediated gene transduction, and chromatin immunoprecipitation assay were used to study the mechanism of TGFbeta1 regulation of CYP7A1 gene transcription. RESULTS: TGFbeta1 inhibited the mRNA expression of CYP7A1 and bile acid synthesis in HepG2 cells and primary human hepatocytes. Mothers against decapentaplegic homolog (Smad3) inhibited both CYP7A1 promoter activity and mRNA expression by inhibiting
Li Tiangang; Chiang John Y L
Gastroenterology
2007
2007-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1053/j.gastro.2007.08.042" target="_blank" rel="noreferrer noopener">10.1053/j.gastro.2007.08.042</a>
Phosphatidylinositide 3-kinase regulates angiotensin II-induced cytosolic phospholipase A2 activity and growth in vascular smooth muscle cells.
Angiotensin II/*metabolism; Animals; Arachidonic Acid/metabolism; Arachidonic Acids/pharmacology; Blotting; Cells; Chromones/pharmacology; Cultured; Enzyme Inhibitors/pharmacology; Flavonoids/pharmacology; Group IV Phospholipases A2; Male; Mitogen-Activated Protein Kinases/metabolism; Morpholines/pharmacology; Muscle; Phosphatidylinositol 3-Kinases/*physiology; Phospholipases A/*metabolism; Phospholipases A2; Phosphorylation; Rats; Smooth; Sprague-Dawley; Vascular/drug effects/*growth & development; Western
Angiotensin (Ang) II via the AT(1) receptor acts as a mitogen in vascular smooth muscle cells (VSMC) through stimulation of multiple signaling mechanisms, including tyrosine kinases and mitogen-activated protein kinase (MAPK). In addition, cytosolic phospholipase A(2)(cPLA(2))-dependent release of arachidonic acid (AA) is linked to VSMC growth and we have reported that Ang II stimulates cPLA(2) activity via the AT(1) receptor. The coupling of Ang II to the activation of cPLA(2) appears to involve mechanisms both upstream and downstream of MAPK such that AA stimulates MAPK activity which phosphorylates cPLA(2) to further enhance AA release. However, the upstream mechanisms responsible for activation of cPLA(2) are not well-defined. One possibility includes phosphatidylinositide
Silfani Tonous N; Freeman Ernest J
Archives of biochemistry and biophysics
2002
2002-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/S0003-9861(02)00066-8" target="_blank" rel="noreferrer noopener">10.1016/S0003-9861(02)00066-8</a>
The effects of anticonvulsant drugs on long-term potentiation (LTP) in the rat hippocampus.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Anticonvulsants/*pharmacology; Calcium Channel Blockers/pharmacology; Enzyme Inhibitors/pharmacology; Excitatory Amino Acid Agonists/pharmacology; Female; Hippocampus/*drug effects; Isoquinolines/pharmacology; Long-Term Potentiation/*drug effects; Male; Membrane Potentials/drug effects; N-Methylaspartate/pharmacology; Piperazines/pharmacology; Protein Kinase C/antagonists & inhibitors; Rats; Synapses/drug effects
In hippocampal CA1 area, there are at least two forms of long-term potentiation (LTP): one is N-methyl-D-aspartate (NMDA) receptor-dependent LTP (NMDA LTP), which is induced with a 25 Hz tetanus and blocked by 50 microM
Lee G Y; Brown L M; Teyler T J
Brain research bulletin
1996
1996
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0361-9230(95)02041-1" target="_blank" rel="noreferrer noopener">10.1016/0361-9230(95)02041-1</a>
NMDA receptor-independent LTP in basal versus apical dendrites of CA1 pyramidal cells in rat hippocampal slice.
Animals; Calcium Channel Blockers/pharmacology; Dendrites/*physiology; Electric Stimulation; Enzyme Inhibitors/pharmacology; Genistein/pharmacology; Hippocampus/cytology/*physiology; In Vitro Techniques; Inbred Strains; Long-Term Potentiation/drug effects/*physiology; Male; N-Methyl-D-Aspartate/*physiology; Phenols/pharmacology; Protein-Tyrosine Kinases/antagonists & inhibitors; Pyramidal Cells/*physiology; Rats; Receptors; Verapamil/pharmacology
The ability of hippocampal CA1 basal synapses to express N-methyl-D-aspartate (NMDA) receptor-independent long-term potentiation (non-NMDA LTP) was studied and compared to the simultaneously induced apical dendritic non-NMDA LTP. Non-NMDA LTP in basal and apical dendrites was induced using stimulation pattern similar to the sharp wave-associated CA3 bursts. Basal dendritic non-NMDA LTP was input-specific and displayed similar development and magnitude to the apical dendritic non-NMDA LTP. Both apical and basal dendritic non-NMDA potentiations were inhibited by the voltage-dependent calcium channel (VDCC) inhibitor verapamil and the tyrosine kinase inhibitors genistein and levandustin A. However, the difference in the degree and time course of these inhibitions suggests involvement of distinct mechanisms in the two dendritic subfields.
Cavus I; Teyler T J
Hippocampus
1998
1905-6
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/(SICI)1098-1063(1998)8:4%3C373::AID-HIPO5%3E3.0.CO;2-I" target="_blank" rel="noreferrer noopener">10.1002/(SICI)1098-1063(1998)8:4%3C373::AID-HIPO5%3E3.0.CO;2-I</a>