Tissue kallikrein gene polymorphisms induce no change in endothelium-dependent or independent vasodilation in hypertensive and normotensive subjects.
BACKGROUND
Tissue kallikrein (TK) generates Lys-bradykinin, which is then converted to bradykinin and releases nitric oxide (NO) from endothelial cells via B2 receptors. TK gene inactivation in mice causes severe endothelial dysfunction, which is also a hallmark of human primary hypertension (PH). Healthy carriers of a loss-of-function Arg to His substitution at position 53 (R53H) of the TK gene exhibit paradoxical arterial eutrophic remodeling. We therefore investigated the impact of this and other TK gene single nucleotide polymorphisms (SNPs) on endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIV) in PH patients and normotensive (NT) subjects.


METHODS
The TK gene SNPs were genotyped blind to the phenotype by sequencing. We compared EDV and EIV vasodilatation across TK genotypes in 131 uncomplicated PH patients and 51 healthy NT subjects. EDV and EIV were assessed as the forearm blood flow response to a graded infusion of acetylcholine and sodium nitroprusside, respectively. We also evaluated the impact of the SNPs on NO-mediated EDV and on reactive oxygen species (ROS)-induced NO breakdown with the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine or vitamin C, respectively.


RESULTS
Genotypes and allele frequencies were in Hardy-Weinberg equilibrium and similar in PH and NT. EDV was lower in PH patients than in NT subjects. No TK genotype affected either EDV or EIV per se, or via interaction with gender and age. NO inhibition and scavenging of ROS showed no TK genotype effect on EDV. Similar conclusions were obtained with haplotype analysis.


CONCLUSIONS
These results do not support the contention that TK gene SNPs have a major impact in determining NO-mediated responses to acetylcholine.
Rossi
Gian Paolo
GP
DMCS Internal Medicine 4, University of Padova, Padova, Italy. gianpaolo.rossi@unipd.it
Taddei
Stefano
S
Ghiadoni
Lorenzo
L
Virdis
Agostino
A
Zavattiero
Silvia
S
Favilla
Stefania
S
Versari
Daniele
D
Sudano
Isabella
I
Azizi
Michel
M
Vedie
Benoit
B
Pessina
Achille C
AC
Salvetti
Antonio
A
Jeunemaitre
Xavier
X
D000328:Adult; D001916:Brachial Artery / Q000503:physiopathology*; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020840:Tissue Kallikreins / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics*
D009569:Nitric Oxide; D020840:Tissue Kallikreins