Detrimental effects of Bartonella henselae are counteracted by l-arginine and nitric oxide in human endothelial progenitor cells

The recruitment of circulating endothelial progenitor cells (EPCs) might have a beneficial effect on the clinical course of several diseases. Endothelial damage and detachment of endothelial cells are known to occur in infection, tissue ischemia, and sepsis. These detrimental effects in EPCs are unknown. Here we elucidated whether human EPCs internalize Bartonella henselae constituting a circulating niche of the pathogen. B. henselae invades EPCs as shown by gentamicin protection assays and transmission electron microscopy (TEM). Dil-Ac-LDL/lectin double immunostaining and fluorescence-activated cell sorting (FACS) analysis of EPCs revealed EPC bioactivity after infection with B. henselae. Nitric oxide (NO) and its precursor l-arginine (l-arg) exert a plethora of beneficial effects on vascular function and modulation of immune response. Therefore, we tested also the hypothesis that l-arg (1–30 mM) would affect the infection of B. henselae or tumor necrosis factor (TNF) in EPCs. Our data provide evidence that l-arg counteracts detrimental effects induced by TNF or Bartonella infections via NO (confirmed by DETA-NO and L-NMMA experiments) and by modulation of p38 kinase phosphorylation. Microarray analysis indicated several genes involved in immune response were differentially expressed in Bartonella-infected EPCs, whereas these genes returned in steady state when cells were exposed to sustained doses of l-arg. This mechanism may have broad therapeutic applications in tissue ischemia, angiogenesis, immune response, and sepsis.

[1]  C. Napoli,et al.  Therapeutic approaches in vascular repair induced by adult bone marrow cells and circulating progenitor endothelial cells. , 2007, Current pharmaceutical design.

[2]  J. Cuevas,et al.  Bartonella-induced endothelial cell proliferation is mediated by release of calcium from intracellular stores. , 2007, DNA and cell biology.

[3]  N. Deutz,et al.  Exogenous arginine in sepsis , 2007, Critical care medicine.

[4]  A. Cope,et al.  Nitric oxide, chronic inflammation and autoimmunity. , 2007, Immunology letters.

[5]  C. Napoli,et al.  Bone marrow cell-mediated cardiovascular repair: potential of combined therapies. , 2007, Trends in molecular medicine.

[6]  H. Algood,et al.  l-Arginine Availability Regulates Inducible Nitric Oxide Synthase-Dependent Host Defense against Helicobacter pylori , 2007, Infection and Immunity.

[7]  C. Napoli,et al.  Comparison between total endothelial progenitor cell isolation versus enriched Cd133+ culture. , 2007, Journal of biochemistry.

[8]  R. Martindale,et al.  Arginine in the critical care setting. , 2007, The Journal of nutrition.

[9]  C. Napoli,et al.  Comparison between total endothelial progenitor cell isolation versus enriched Cd133+ culture , 2007 .

[10]  Claudio Napoli,et al.  Nutrition, physical activity, and cardiovascular disease: an update. , 2007, Cardiovascular research.

[11]  C. Napoli,et al.  Nitric oxide and atherosclerosis: an update. , 2006, Nitric oxide : biology and chemistry.

[12]  C. Natanson,et al.  Preclinical trial of l-arginine monotherapy alone or with N-acetylcysteine in septic shock* , 2006, Critical care medicine.

[13]  K. Kudsk.  Immunonutrition in surgery and critical care. , 2006, Annual review of nutrition.

[14]  D. Kim.  Circulating endothelial progenitor cells. , 2005, The New England journal of medicine.

[15]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[16]  C. Napoli,et al.  Beneficial effects of concurrent autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the mouse hindlimb. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Garmy-Susini,et al.  Circulating endothelial progenitor cells , 2005, British Journal of Cancer.

[18]  H. Einsele,et al.  Infection of human CD34+ progenitor cells with Bartonella henselae results in intraerythrocytic presence of B. henselae. , 2005, Blood.

[19]  C. Dehio.  Bartonella–host-cell interactions and vascular tumour formation , 2005, Nature Reviews Microbiology.

[20]  C. Napoli,et al.  New trends in anti-atherosclerotic agents. , 2005, Current medicinal chemistry.

[21]  A. Zeiher,et al.  p38 Mitogen-Activated Protein Kinase Downregulates Endothelial Progenitor Cells , 2005, Circulation.

[22]  K. Alitalo,et al.  Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections , 2005, Circulation.

[23]  D. Raoult,et al.  Detection of Bartonella quintana by Direct Immunofluorescence Examination of Blood Smears of a Patient with Acute Trench Fever , 2004, Journal of Clinical Microbiology.

[24]  S. Dimmeler,et al.  Endothelial Progenitor Cells: Characterization and Role in Vascular Biology , 2004, Circulation research.

[25]  C. Napoli,et al.  Nitric oxide-releasing drugs. , 2003, Annual review of pharmacology and toxicology.

[26]  G. Pruneri,et al.  Circulating endothelial cells as a novel marker of angiogenesis. , 2003, Advances in experimental medicine and biology.

[27]  W. Goebel,et al.  Interaction of human hematopoietic stem cells with bacterial pathogens. , 2002, Blood.

[28]  D. Raoult,et al.  Bartonella: new explanations for old diseases. , 2002, Journal of medical microbiology.

[29]  Dawn M. Nekorchuk,et al.  Bartonella-associated endothelial proliferation depends on inhibition of apoptosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Heyland,et al.  Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. , 2001, JAMA.

[31]  C. Lanz,et al.  Invasion and Persistent Intracellular Colonization of Erythrocytes , 2001, The Journal of experimental medicine.

[32]  S. Bode-Böger,et al.  The clinical pharmacology of L-arginine. , 2001, Annual review of pharmacology and toxicology.

[33]  G. Corso,et al.  Randomized, double-blind, placebo-controlled study of arginine supplementation in chronic renal failure. , 1999, Kidney international.

[34]  T. Blaschke,et al.  Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. , 1999, British journal of clinical pharmacology.

[35]  C. Lanz,et al.  Interaction of Bartonella henselae with endothelial cells results in bacterial aggregation on the cell surface and the subsequent engulfment and internalisation of the bacterial aggregate by a unique structure, the invasome. , 1997, Journal of cell science.

[36]  W. Burchert,et al.  Dose-related effect of intravenous L-arginine on muscular blood flow of the calf in patients with peripheral vascular disease: a H215O positron emission tomography study. , 1997, Clinical science.

[37]  A. Mantovani,et al.  Cytokine regulation of endothelial cell function: from molecular level to the bedside. , 1997, Immunology today.

[38]  B. Anderson,et al.  Bartonella spp. as emerging human pathogens , 1997, Clinical microbiology reviews.

[39]  D. Tsikas,et al.  L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study. , 1996, Circulation.

[40]  D Nadal,et al.  Intracellular location of Bartonella henselae cocultivated with Vero cells and used for an indirect fluorescent-antibody test , 1995, Clinical and diagnostic laboratory immunology.