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.
Salvatore
Paola
P
Department of Cellular and Molecular Biology and Pathology Luigi Califano, School of Biotechnological Sciences, Federico II University of Naples, Naples 80131, Italy.
Casamassimi
Amelia
A
Sommese
Linda
L
Fiorito
Carmela
C
Ciccodicola
Alfredo
A
Rossiello
Raffaele
R
Avallone
Bice
B
Grimaldi
Vincenzo
V
Costa
Valerio
V
Rienzo
Monica
M
Colicchio
Roberta
R
Williams-Ignarro
Sharon
S
Pagliarulo
Caterina
C
Prudente
Maria Evelina
ME
Abbondanza
Ciro
C
Lamberti
Florentia
F
Baroni
Adone
A
Buommino
Elisabetta
E
Farzati
Bartolomeo
B
Tufano
Maria Antonietta
MA
Ignarro
Louis Joseph
LJ
Napoli
Claudio
C
D001120:Arginine / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects; D018416:Bartonella henselae / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000382:microbiology* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000382:microbiology* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D001120:Arginine; D048051:p38 Mitogen-Activated Protein Kinases