articles+ search results

18 articles+ results

1 - 18
View results as:
Number of results to display per page

1. Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1α [2014]

  • BALL, Molly K, WAYPA, Gregory B, SHAH, Sanjiv J, SCHUMACKER, Paul T, MUNGAI, Paul T, NIELSEN, Jacqueline M, CZECH, Lyubov, DUDLEY, V. Joseph, BEUSSINK, Lauren, DETTMAN, Robert W, BERKELHAMER, Sara K, and STEINHORN, Robin H
  • American journal of respiratory and critical care medicine. 189(3):314-324
Subjects
Pneumology, Pneumologie, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pneumologie, Pneumology, Hypertension artérielle pulmonaire. Coeur pulmonaire aigu. Embolie pulmonaire. Maladies des vaisseaux pulmonaires, Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases, Anesthesie. Reanimation. Transfusion. Therapie cellulaire et therapie genique, Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy, Réanimation. Soins intensifs, Intensive care medicine, Mammalia, Pathologie de l'appareil circulatoire, Cardiovascular disease, Aparato circulatorio patología, Rodentia, Vertebrata, Circulation pulmonaire, Pulmonary circulation, Circulación pulmonar, Facteur transcription HIF1, Transcription factor HIF1, Factor transcripción HIF1, Hypertension artérielle pulmonaire, Pulmonary hypertension, Hipertensión arterial pulmonar, Hypertrophie, Hypertrophy, Hipertrofia, Hypoxie, Hypoxia, Hipoxia, Maladie, Disease, Enfermedad, Modèle animal, Animal model, Modelo animal, Muscle lisse, Smooth muscle, Músculo liso, Oxygène, Oxygen, Oxígeno, Pathologie de l'appareil respiratoire, Respiratory disease, Aparato respiratorio patología, Réanimation, Resuscitation, Reanimación, Régulation, Regulation(control), Regulación, Soin intensif, Intensive care, Cuidado intensivo, Souris, Mouse, Ratón, Vaisseau sanguin, Blood vessel, Vaso sanguíneo, Ventricule droit, Right ventricle, Ventrículo derecho, animal disease models, knock-out mice, pulmonary circulation, and right ventricular hypertrophy
Abstract
Rationale: Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. Objectives: We sought to determine the contribution of HIF-1α in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. Methods: We used mice with homozygous conditional deletion of HIF-1α combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses. Measurements and Main Results: Tamoxifen-induced smooth muscle-specific deletion of HIF-1α attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures. Conclusions: These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.

2. This title is not available for guests. Log in to see the title and access the article.

3. This title is not available for guests. Log in to see the title and access the article.

4. This title is not available for guests. Log in to see the title and access the article.

5. This title is not available for guests. Log in to see the title and access the article.

6. This title is not available for guests. Log in to see the title and access the article.

7. This title is not available for guests. Log in to see the title and access the article.

8. This title is not available for guests. Log in to see the title and access the article.

9. This title is not available for guests. Log in to see the title and access the article.

10. This title is not available for guests. Log in to see the title and access the article.

11. This title is not available for guests. Log in to see the title and access the article.

12. This title is not available for guests. Log in to see the title and access the article.

13. Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms [2010]

  • Sofat, Reecha, Hingorani, Aroon D., Smeeth, Liam, Humphries, Steve E., Talmud, Philippa J., Cooper, Jackie, Shah, Tina, Sandhu, Manjinder S., Ricketts, Sally L., Boekholdt, S. Matthijs, Wareham, Nicholas, Khaw, Kay Tee, Kumari, Meena, Kivimaki, Mika, Marmot, Michael, Asselbergs, Folkert W., van der Harst, Pim, Dullaart, Robin P. F., Navis, Gerjan, van Veldhuisen, Dirk J., van Gilst, Wiek H., Thompson, John F., McCaskie, Pamela, Palmer, Lyle J., Arca, Marcello, Quagliarini, Fabiana, Gaudio, Carlo, Cambien, François, Nicaud, Viviane, Poirer, Odette, Gudnason, Vilmundur, Isaacs, Aaron, Witteman, Jacqueline C. M., van Duijn, Cornelia M., Pencina, Michael, Vasan, Ramachandran S., D'Agostino, Ralph B., Ordovas, Jose, Li, Tricia Y., Kakko, Sakari, Kauma, Heikki, Savolainen, Markku J., Kesäniemi, Y. Antero, Sandhofer, Anton, Paulweber, Bernhard, Sorli, Jose V., Goto, Akimoto, Yokoyama, Shinji, Okumura, Kenji, Horne, Benjamin D., Packard, Chris, Freeman, Dilys, Ford, Ian, Sattar, Naveed, McCormack, Valerie, Lawlor, Debbie A., Ebrahim, Shah, Smith, George Davey, Kastelein, John J. P., Deanfield, John, Casas, Juan P., Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Erasmus MC: University Medical Center Rotterdam, Cardiology and Thorax Surgery, Int.gnsk.med.-Endocrinologie, Int.gnsk.med.-Nefrologie, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Medical Imaging (CMI)
  • Circulation, 121(1), 52 - 62. Lippincott Williams and Wilkins
    Circulation, 121(1), 52 - 62. LIPPINCOTT WILLIAMS & WILKINS
    Circulation (Baltimore), 121(1), 52 - 62
    SOFAT, Reecha ; Hingorani, Aroon D. ; Smeeth, Liam ; Humphries, Steve E. ; Talmud, Philippa J. ; Cooper, Jackie ; Shah, Tina ; Sandhu, Manjinder S. ; Ricketts, Sally L. ; Boekholdt, S. Matthijs ; Wareham, Nicholas ; Khaw Kay, Tee ; Kumari, Meena ; Kivimaki, Mika ; Marmot, Michael ; Asselbergs, Folkert W. ; Van der Harst, Pim ; Dullaart, Robin P.F. ; Navis, Gerjanvan ; Veldhuisen, Dirk J. ; Van Gilst, Wiek H. ; Thompson, John F. ; McCaskie, Pamela ; Palmer, Lyle J. ; Arca, Marcello ; Quagliarini, Fabiana ; Gaudio, Carlo ; Cambien, François ; Nicaud, Viviane ; Poirer, Odette ; Gudnason, Vilmundur ; Isaacs, Aaron ; Witteman, Jacqueline C.M. ; van Duijn, Cornelia M., Pencina, Michael ; Vasan, Ramachandran S. ; D'Agostino, Ralph B. ; Ordovas, Jose ; Li, Tricia Y. ; Kakko, Sakari ; Kauma, Heikki ; Savolainen, Markku J. ; Kesäniemi, Antero ; Sandhofer, Anton ; Paulweber, Bernhard ; Sorli Guerola, Jose Vicente ; Goto, Akimoto ; Yokoyama, Shinji ; Okumura, Kenji ; Horne, Benjamin D. ; Packard, Chris ; Freeman, Dilys ; Ford, Ian ; Sattar, Naveed ; McCormack, Valerie ; Lawlor, Debbie A. ; Ebrahim, Shah ; Smith, George Davey ; Kastelein, John J.P. ; Deanfield, John ; Casas, Juan P., 2010, Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms, Circulation, vol. 121, no. 1, p. 52-62
Subjects
UNESCO::CIENCIAS MÉDICAS ::Medicina interna, ATHEROSCLEROSIS, DISEASE, HDL CHOLESTEROL, lipids (amino acids, peptides, and proteins), high-density lipoproteins, UMCG Approved, UNESCO::CIENCIAS MÉDICAS, HIGH-DENSITY-LIPOPROTEIN, epidemiology, genetics, Genetics, Pharmacology, Epidemiology, High-density lipoproteins, pharmacology, GENOME-WIDE ASSOCIATION, BLOOD-PRESSURE, TORCETRAPIB, MENDELIAN RANDOMIZATION, DOUBLE-BLIND, and LIPID-LEVELS
Abstract
Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans. Sorli Guerola, Jose Vicente, Jose.Sorli@uv.es

14. This title is not available for guests. Log in to see the title and access the article.

15. This title is not available for guests. Log in to see the title and access the article.

16. This title is not available for guests. Log in to see the title and access the article.

17. This title is not available for guests. Log in to see the title and access the article.

18. This title is not available for guests. Log in to see the title and access the article.

Catalog

Books, media, physical & digital resources
See catalog results

Guides

Course- and topic-based guides to collections, tools, and services.
Search """Robin, Jacqueline,""" in all guide pages