The angiotensin-converting enzyme insertion/deletion polymorphism is associated with phagocytic NADPH oxidase-dependent superoxide generation: potential implication in hypertension.
The objective of the present study was to analyse the influence of the ACE (angiotensin-converting enzyme) gene I/D (insertion/deletion) polymorphism on NADPH oxidase-dependent O(2)(*-) (superoxide radical) production, and to investigate the clinical implication of this association in hypertensive subjects. A case-control study was performed in a random sample of the general population composed of 189 normotensive subjects and 223 hypertensive subjects. The ACE polymorphism was determined by PCR. NADPH oxidase-dependent O(2)(*-) production was quantified in phagocytic cells by chemiluminescence. MMP-9 (matrix metalloproteinase-9), a marker of atherosclerosis previously reported to be associated with NADPH oxidase overactivity, was quantified by ELISA in plasma samples. The distribution of genotypes was in Hardy-Weinberg equilibrium. The I/D polymorphism was not associated with hypertension. NADPH oxidase-dependent O(2)(*-) production was significantly higher in D/D (deletion/deletion) than in I/I (insertion/insertion) and I/D, both in normotensive and hypertensive subjects. Interestingly, plasma levels of angiotensin II were significantly higher in D/D than in I/I and I/D, both in normotensive and hypertensive subjects. Plasma levels of MMP-9 and systolic blood pressure values were significantly higher in D/D than in I/I and I/D hypertensive subjects, whereas no differences were found among genotypes in normotensive subjects. Interestingly, NADPH oxidase-dependent O(2)(*-) production positively associated with plasma MMP-9 levels in hypertensive subjects, which remained significant after adjustment for age and gender. In conclusion, in the present study we have reported for the first time an association of the D/D genotype of the ACE I/D polymorphism with phagocytic NADPH oxidase-mediated O(2)(*-) overproduction. Within the group of hypertensive patients, D/D cases also associated with increased blood pressure values and with enhanced plasma levels of MMP-9.
San José
Gorka
G
Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.
Fortuño
Ana
A
Moreno
María U
MU
Robador
Pablo A
PA
Bidegain
Julen
J
Varo
Nerea
N
Beloqui
Oscar
O
Díez
Javier
J
Zalba
Guillermo
G
D016022:Case-Control Studies; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D019255:NADPH Oxidases / Q000378:metabolism / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010586:Phagocytes / Q000378:metabolism; D011110:Polymorphism, Genetic; D013481:Superoxides / Q000378:metabolism*
D008055:Lipids; D013481:Superoxides; D019255:NADPH Oxidases; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D020780:Matrix Metalloproteinase 9