Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

Background The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. Methodology/Principal Findings To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment. Conclusion/Significance Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure.

[1]  M. Iglarz,et al.  At the heart of tissue: endothelin system and end-organ damage. , 2010, Clinical science.

[2]  Yusu Gu,et al.  Loss of Enigma Homolog Protein Results in Dilated Cardiomyopathy , 2010, Circulation research.

[3]  S. Mani,et al.  Hypertrophic Stimulation Increases β-actin Dynamics in Adult Feline Cardiomyocytes , 2010, PloS one.

[4]  A. McCulloch,et al.  An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. , 2008, The Journal of clinical investigation.

[5]  M. Essop.  Cardiac metabolic adaptations in response to chronic hypoxia , 2007, The Journal of physiology.

[6]  M. J. Wagner,et al.  Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. , 2007, Cardiovascular research.

[7]  N. Sengupta,et al.  IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development , 2007, Proceedings of the National Academy of Sciences.

[8]  G. Tsujimoto,et al.  α1-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension , 2007 .

[9]  E. Füchtbauer,et al.  AQP7 is localized in capillaries of adipose tissue, cardiac and striated muscle: implications in glycerol metabolism. , 2007, American journal of physiology. Renal physiology.

[10]  S. Nielsen,et al.  Characterization of a rat model of right-sided heart failure induced by pulmonary trunk banding , 2007 .

[11]  G. Tsujimoto,et al.  Alpha1-adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension. , 2007, American journal of physiology. Heart and circulatory physiology.

[12]  A. Dai,et al.  Hypoxia Induces Transforming Growth Factor-β1 Gene Expression in the Pulmonary Artery of Rats via Hypoxia-inducible Factor-1α , 2007 .

[13]  A. Dai,et al.  Hypoxia induces transforming growth factor-beta1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1alpha. , 2007, Acta biochimica et biophysica Sinica.

[14]  N. Voelkel,et al.  Gene expression profiling in pulmonary hypertension. , 2007, Proceedings of the American Thoracic Society.

[15]  S. Salvi,et al.  Enhanced α1-adrenergic trophic activity in pulmonary artery of hypoxic pulmonary hypertensive rats , 2006 .

[16]  C. Ricachinevsky,et al.  Treatment of pulmonary arterial hypertension. , 2006, Jornal de pediatria.

[17]  E. Hardeman,et al.  Cardiac aquaporin expression in humans, rats, and mice. , 2006, American journal of physiology. Heart and circulatory physiology.

[18]  J. Litz,et al.  Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1α activity and vascular endothelial growth factor expression in small cell lung cancer cells , 2006, Molecular Cancer Therapeutics.

[19]  Marc A Pfeffer,et al.  Controversies in ventricular remodelling , 2006, The Lancet.

[20]  S. Salvi,et al.  Enhanced alpha1-adrenergic trophic activity in pulmonary artery of hypoxic pulmonary hypertensive rats. , 2006, American journal of physiology. Heart and circulatory physiology.

[21]  E. Masini,et al.  Oxidative Stress by Monoamine Oxidase Mediates Receptor-Independent Cardiomyocyte Apoptosis by Serotonin and Postischemic Myocardial Injury , 2005, Circulation.

[22]  P. Steendijk,et al.  Right Atrial and Ventricular Adaptation to Chronic Right Ventricular Pressure Overload , 2005, Circulation.

[23]  R. Glenny,et al.  Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. , 2005, Physiological genomics.

[24]  B. Ylstra,et al.  Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. , 2005, Physiological genomics.

[25]  D. Pimentel,et al.  A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor‐independent ROS generation , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  K. Chin,et al.  The right ventricle in pulmonary hypertension , 2005, Coronary artery disease.

[27]  S. Kihara,et al.  Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. P. Nana-Sinkam,et al.  Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. , 2004, American journal of respiratory and critical care medicine.

[29]  P. Razeghi,et al.  404-4 Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy , 2004 .

[30]  P. Razeghi,et al.  Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy. , 2001, American journal of physiology. Heart and circulatory physiology.

[31]  Y. Wakayama,et al.  Expression and localization of aquaporin 7 in normal skeletal myofiber , 2004, Cell and Tissue Research.

[32]  M. Mulvany,et al.  The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats , 2004, British journal of pharmacology.

[33]  E. Olson,et al.  Cardiac hypertrophy: the good, the bad, and the ugly. , 2003, Annual review of physiology.

[34]  W. Kuebler,et al.  The prostaglandins epoprostenol and iloprost increase left ventricular contractility in vivo , 2003, Intensive Care Medicine.

[35]  G. Hasenfuss,et al.  Mechanical Load-Dependent Regulation of Gene Expression in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat , 2003, Circulation research.

[36]  E. Billett,et al.  A comparative study of the expression of monoamine oxidase-A and -B mRNA and protein in non-CNS human tissues , 2003, Cell and Tissue Research.

[37]  E. Solary,et al.  Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload. , 2002, Biochimica et biophysica acta.

[38]  D. Leroith,et al.  Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. , 2001, Endocrinology.

[39]  E. Billett,et al.  Cellular localization of monoamine oxidase A and B in human tissues outside of the central nervous system , 2001, Cell and Tissue Research.

[40]  N. Voelkel,et al.  Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension: A Gene Microarray Analysis , 2001, Circulation research.

[41]  H. Park,et al.  Enhanced gene expression of renin-angiotensin system, TGF-beta1, endothelin-1 and nitric oxide synthase in right-ventricular hypertrophy. , 2001, Pharmacological research.

[42]  G. Dorn,et al.  Cytoplasmic signaling pathways that regulate cardiac hypertrophy. , 2001, Annual review of physiology.

[43]  C. Lee,et al.  Identification of differentially expressed genes in cardiac hypertrophy by analysis of expressed sequence tags. , 2000, Genomics.

[44]  K. Mehta,et al.  Tissue transglutaminase: an enzyme with a split personality. , 1999, The international journal of biochemistry & cell biology.

[45]  G. Dorn,et al.  Cardiac Specific Overexpression of Transglutaminase II (Gh) Results in a Unique Hypertrophy Phenotype Independent of Phospholipase C Activation* , 1999, The Journal of Biological Chemistry.

[46]  S. P. Fodor,et al.  High density synthetic oligonucleotide arrays , 1999, Nature Genetics.

[47]  G. Montalescot,et al.  Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure. , 1998, The American journal of cardiology.

[48]  John W. Adams,et al.  Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  F. Lallemand,et al.  Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. , 1997, Circulation.

[50]  S. Oparil,et al.  Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. , 1995, Journal of applied physiology.

[51]  R. Lefkowitz,et al.  Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. , 1994, Proceedings of the National Academy of Sciences of the United States of America.