Altered Gene Expression Pattern in Peripheral Blood Leukocytes from Patients with Arterial Hypertension

Abstract:  The role of various inflammatory mechanisms and oxidative stress in the development of atherosclerosis and arterial hypertension (AH) has been increasingly acknowledged during recent years. Hypertension per se or factors that cause hypertension along with other complications lead to infiltration of activated leukocytes in the vascular wall, where these cells contribute to the development of vascular injury by releasing cytokines, oxygen radicals, and other toxic mediators. However, molecular mechanisms underlying leukocyte activation at transcriptional level in AH are still far from being clear. To solve this problem we employed cDNA microarray technology to reveal the differences in gene expression in peripheral blood leukocytes from patients with AH compared with healthy individuals. The microarray data were verified by a semi‐quantitative RT‐PCR method. We found 25 genes with differential expression in leukocytes from AH patients among which 21 genes were upregulated and 4 genes were downregulated. These genes are implicated in apoptosis (CASP2, CASP4, and CASP8, p53, UBID4, NAT1, and Fte‐1), inflammatory response (CAGC, CXCR4, and CX3CR1), control of MAP kinase function (PYST1, PAC1, RAF1, and RAFB1), vesicular trafficking of molecules among cellular organelles (GDI‐1 and GDI‐2), cell redox homeostasis (GLRX), cellular stress (HSPA8 and HSP40), and other processes. Gene expression pattern of the majority of genes was similar in AH patients independent of the disease stage and used hypotensive therapy, but was clearly different from that of normotensive subjects.

[1]  D. Alessi,et al.  Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual‐specificity phosphatase. , 1996, The EMBO journal.

[2]  Qingbo Xu,et al.  Biomechanical stress-induced signaling in smooth muscle cells: an update. , 2003, Current vascular pharmacology.

[3]  A. Kakizuka,et al.  Protein precipitation: a common etiology in neurodegenerative disorders? , 1998, Trends in genetics : TIG.

[4]  G. Plante Vascular response to stress in health and disease. , 2002, Metabolism: clinical and experimental.

[5]  P. Liebmann,et al.  Prolonged alpha-adrenergic stimulation causes changes in leukocyte distribution and lymphocyte apoptosis in the rat , 2001, Journal of Neuroimmunology.

[6]  T. Vogl,et al.  Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. , 2003, Trends in immunology.

[7]  O. Yoshie,et al.  Fractalkine in Vascular Biology: From Basic Research to Clinical Disease , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[8]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. de Champlain,et al.  Transient involvement of endothelin in hypertrophic remodeling of small arteries , 2001, Journal of hypertension.

[10]  H. Naora,et al.  Involvement of ribosomal proteins in regulating cell growth and apoptosis: Translational modulation or recruitment for extraribosomal activity? , 1999, Immunology and cell biology.

[11]  C. Haslett,et al.  Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. , 1986, The Journal of clinical investigation.

[12]  E. Conway de Macario,et al.  Sick chaperones, cellular stress, and disease. , 2005, The New England journal of medicine.

[13]  S. Sakamoto,et al.  Inhibition of poly(ADP-ribose) polymerase activity by Bcl-2 in association with the ribosomal protein S3a. , 2002, Biochemistry.

[14]  A. Barzilai,et al.  Glutaredoxin Protects Cerebellar Granule Neurons from Dopamine-induced Apoptosis by Dual Activation of the Ras-Phosphoinositide 3-Kinase and Jun N-terminal Kinase Pathways* , 2001, The Journal of Biological Chemistry.

[15]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[16]  Richard T. Lee,et al.  Identification of mechanically induced genes in human monocytic cells by DNA microarrays , 2002, Journal of hypertension.

[17]  C. Der,et al.  The Mitogen-activated Protein Kinase Phosphatases PAC1, MKP-1, and MKP-2 Have Unique Substrate Specificities and Reduced Activity in Vivo toward the ERK2 sevenmaker Mutation (*) , 1996, The Journal of Biological Chemistry.

[18]  C. Kunsch,et al.  Oxidative stress as a regulator of gene expression in the vasculature. , 1999, Circulation research.

[19]  S. Sela,et al.  Participation of peripheral polymorphonuclear leukocytes in the oxidative stress and inflammation in patients with essential hypertension. , 1997, American journal of hypertension.

[20]  H. Dige-Petersen,et al.  Is cardiovascular remodeling in patients with essential hypertension related to more than high blood pressure? A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. , 2002, American heart journal.

[21]  K. Chong,et al.  Stable overexpression of the constitutive form of heat shock protein 70 confers oxidative protection. , 1998, Journal of molecular and cellular cardiology.

[22]  T. Nakajima,et al.  Detection and Delineation of CXCR-4 (Fusin) as an Entry and Fusion Cofactor for T Cell-Tropic HIV-1 by Three Different Monoclonal Antibodies , 1998, The Journal of Immunology.

[23]  A. Holmgren,et al.  Thioredoxin and glutaredoxin systems. , 2019, The Journal of biological chemistry.

[24]  T. Resink,et al.  Activation of human peripheral monocytes by angiotensin II , 1994, FEBS letters.

[25]  M. Faty,et al.  Purification of a dichlorophenol-indophenol oxidoreductase from rat and bovine synaptic membranes: tight complex association of a glyceraldehyde-3-phosphate dehydrogenase isoform, TOAD64, enolase-gamma and aldolase C. , 1997, The Biochemical journal.

[26]  Ali G. Gharavi,et al.  Molecular Mechanisms of Human Hypertension , 2001, Cell.

[27]  M. Neurath,et al.  RAGE Mediates a Novel Proinflammatory Axis A Central Cell Surface Receptor for S100/Calgranulin Polypeptides , 1999, Cell.

[28]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[29]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.