High expression of the cGMP-specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils.
Modulation of intracellular cyclic guanosine monophosphate (cGMP) may characterize a therapeutic target for sickle cell disease (SCD); cGMP-dependent signalling may be important for erythroid foetal haemoglobin induction and exert anti-inflammatory functions in leucocytes. As the inhibition of phosphodiesterases (PDEs), which regulate intracellular cGMP, can result in tissue-specific elevation of cGMP, we studied the gene expressions of cGMP-specific PDEs (-1A, -5A and -9A) in the reticulocytes and neutrophils of healthy controls, steady-state SCD patients and SCD patients on hydroxycarbamide therapy (SCDHC). PDE9A gene expression was found in numerous cell types; however, high expression was found in neutrophils, reticulocytes, CD34(+)-derived erythroid cells and K562 erythroleukaemic cells, indicating a high haematopoietic cell expression. PDE9A gene expression was, however, significantly higher in the reticulocytes and neutrophils of SCD individuals, compared to control cells; Western blotting confirmed the production of PDE9A protein in SCD neutrophils and K562 cells. Inhibition of PDE9A enzyme with the specific inhibitor, BAY73-6691, significantly increased production of the gamma-globin gene (HBG) in K562 cells and reversed the increased adhesive properties of SCD neutrophils. Since elevation of haematopoietic intracellular cGMP may be beneficial in SCD, the relatively limited tissue distribution of PDE9A suggests that it could represent a novel drug target worthy of further study.
Almeida
Camila Bononi
CB
Haematology and Haemotherapy Centre, State University of Campinas - UNICAMP, Sao Paulo, SP, Brazil.
Traina
Fabiola
F
Lanaro
Carolina
C
Canalli
Andreia A
AA
Saad
Sara T O
ST
Costa
Fernando F
FF
Conran
Nicola
N
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000201:enzymology*; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use; D001938:Brazil; D016022:Case-Control Studies; D041905:Erythroid Cells / Q000201:enzymology; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000201:enzymology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012156:Reticulocytes / Q000201:enzymology; D055545:gamma-Globins / Q000378:metabolism
D000986:Antisickling Agents; C507056:BAY 73-6691; D011720:Pyrazoles; D011743:Pyrimidines; D055545:gamma-Globins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006918:Hydroxyurea