Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells.

Extracellular acidosis (EA) has profound effects on vascular homeostasis, including vascular bed-specific alterations in vascular tone. Regulation of gene expression by EA has been observed in a variety of cells including vascular endothelial cells. Whether EA regulates gene expression in vascular smooth muscle cells (VSMCs) is not known. Heme oxygenase (HO)-1 is expressed in vascular cells, and its expression is regulated by cellular stressors such as heat, radiation, and hypoxia. Increased HO-1 expression in VSMCs leads to increased production of CO and its second messenger cGMP, which are important regulators of vascular tone and paracrine interactions in the vasculature. We examined whether EA regulates the expression of HO-1 in VSMCs. Exposure of VSMCs to acidic medium (pH 6.8) significantly increased HO-1 mRNA and protein compared with exposure to medium of physiological pH (pH 7.4). The acidic induction of HO-1 expression was time dependent and involved both transcriptional activation of the HO-1 gene and enhanced stability of HO-1 mRNA. Nitric oxide did not appear to mediate this response. We conclude that HO-1 is transcriptionally and posttranscriptionally upregulated by EA in VSMCs. This induction is time dependent and reversible. We speculate that EA, as an important tissue and cellular stressor for VSMCs, may elicit changes in gene expression patterns that contribute to the maintenance or disruption of vascular homeostasis.

[1]  R. Wersto,et al.  Intracellular acidosis‐activated p38 MAPK signaling and its essential role in cardiomyocyte hypoxic injury , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  M. Zheng,et al.  Acidosis-induced p38 MAPK activation and its implication in regulation of cardiac contractility. , 2004, Acta pharmacologica Sinica.

[3]  T. Brennan,et al.  Changes in Tissue pH and Temperature after Incision Indicate Acidosis May Contribute to Postoperative Pain , 2004, Anesthesiology.

[4]  L. Gunaratnam,et al.  HIF activation by pH-dependent nucleolar sequestration of VHL , 2004, Nature Cell Biology.

[5]  F. Abboud,et al.  Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Robert J. Gillies,et al.  Acidic pH enhances the invasive behavior of human melanoma cells , 1996, Clinical & Experimental Metastasis.

[7]  Jianping Wu,et al.  Hypercapnic Acidosis Activates KATP Channels in Vascular Smooth Muscles , 2003, Circulation research.

[8]  L. Chao,et al.  Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats. , 2002, American journal of physiology. Endocrinology and metabolism.

[9]  M. Cutaia,et al.  Inhibition of apoptosis in pulmonary endothelial cells by altered pH, mitochondrial function, and ATP supply. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[10]  L. Agulló,et al.  Hypoxia and acidosis impair cGMP synthesis in microvascular coronary endothelial cells. , 2002, American journal of physiology. Heart and circulatory physiology.

[11]  M. Wahl,et al.  Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH. , 2002, Endothelium : journal of endothelial cell research.

[12]  N. Curthoys,et al.  Mechanism of increased renal gene expression during metabolic acidosis. , 2001, American journal of physiology. Renal physiology.

[13]  T. Minamino,et al.  Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  N. Curthoys,et al.  Identification of ζ-Crystallin/NADPH:Quinone Reductase as a Renal Glutaminase mRNA pH Response Element-binding Protein* , 2001, The Journal of Biological Chemistry.

[15]  M. Minami,et al.  Global Ischemia Induces Expression of Acid-Sensing Ion Channel 2a in Rat Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[16]  R. Nagai,et al.  Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusion in vivo. , 2000, Biochemical and biophysical research communications.

[17]  L. Shimoda,et al.  L-type Ca(2+) channels, resting [Ca(2+)](i), and ET-1-induced responses in chronically hypoxic pulmonary myocytes. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[18]  B. Demple,et al.  Nitric Oxide-inducible Expression of Heme Oxygenase-1 in Human Cells , 2000, The Journal of Biological Chemistry.

[19]  I. Fidler,et al.  Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. , 2000, Cancer research.

[20]  S. Wray,et al.  Interactions Between Ca2+ and H+ and Functional Consequences in Vascular Smooth Muscle , 2000 .

[21]  F. Facchiano,et al.  Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. , 2000, Circulation research.

[22]  S. Wray,et al.  Interactions between Ca(2+) and H(+) and functional consequences in vascular smooth muscle. , 2000, Circulation research.

[23]  A. Choi,et al.  Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. , 1999, The Journal of clinical investigation.

[24]  N. Webster,et al.  Acidosis and tissue hypoxia in the critically ill: how to measure it and what does it mean. , 1999, Critical reviews in clinical laboratory sciences.

[25]  L. Turka,et al.  Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes , 1998, Nature Medicine.

[26]  R. Colvin,et al.  Expression of heme oxygenase-1 can determine cardiac xenograft survival , 1998, Nature Medicine.

[27]  G. Semenza,et al.  Carbon Monoxide and Nitric Oxide Suppress the Hypoxic Induction of Vascular Endothelial Growth Factor Gene via the 5′ Enhancer* , 1998, The Journal of Biological Chemistry.

[28]  Carole Philippe,et al.  Low Environmental pH Is Responsible for the Induction of Nitric-oxide Synthase in Macrophages , 1998, The Journal of Biological Chemistry.

[29]  S. Kourembanas,et al.  Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells* , 1997, The Journal of Biological Chemistry.

[30]  A. Choi,et al.  Regulation of heme oxygenase-1 gene expression in vascular smooth muscle cells by nitric oxide. , 1997, American journal of physiology. Lung cellular and molecular physiology.

[31]  C. T. Wagner,et al.  Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. , 1997, The Journal of clinical investigation.

[32]  C. Hsieh,et al.  Prevention of Hypoxia-Induced Pulmonary Hypertension by Enhancement of Endogenous Heme Oxygenase-1 in the Rat. • 238 , 1997, Pediatric Research.

[33]  G. Semenza,et al.  Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia* , 1997, The Journal of Biological Chemistry.

[34]  C. Patterson,et al.  Induction of Heme Oxygenase-1 Expression in Vascular Smooth Muscle Cells , 1997, The Journal of Biological Chemistry.

[35]  C. Rembold,et al.  Nitroglycerin relaxes rat tail artery primarily by lowering Ca2+ sensitivity and partially by repolarization. , 1996, The American journal of physiology.

[36]  J. Zweier,et al.  pH dependence of neutrophil-endothelial cell adhesion and adhesion molecule expression. , 1996, The American journal of physiology.

[37]  N. Curthoys,et al.  Promoter elements that mediate the pH response of PCK mRNA in LLC-PK1-F+ cells. , 1996, The American journal of physiology.

[38]  A. Choi,et al.  Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. , 1996, American journal of respiratory cell and molecular biology.

[39]  N. Abraham,et al.  The Biological Significance and Physiological Role of Heme Oxygenase , 1996 .

[40]  S. Kourembanas,et al.  Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. , 1995, The Journal of clinical investigation.

[41]  J. Pearson,et al.  Induction of the antioxidant stress proteins heme oxygenase‐1 and MSP23 by stress agents and oxidised LDL in cultured vascular smooth muscle cells , 1995, FEBS letters.

[42]  S. Kourembanas,et al.  Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  G. Harsh,et al.  Transcriptional regulation of the A and B chain genes of platelet-derived growth factor in microvascular endothelial cells. , 1988, The Journal of biological chemistry.

[44]  J. Haveman,et al.  The relevance of tumour pH to the treatment of malignant disease. , 1984, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[45]  P. W. Hochachka,et al.  Protons and anaerobiosis. , 1983, Science.