In the vascular endothelium, nitric oxide (NO) is constitutively
produced from L-arginine by the enzyme endothelial Nitric Oxide
Synthase (eNOS). NO plays a key role in the relaxation of vascular
smooth muscle, inhibits platelets and leukocytes adhesion to the
endothelium, reduces vascular smooth muscle cells migration and
proliferation and limits the oxidation of atherogenic low-density
lipoproteins. Because of these multiple actions, NO plays a central
role in maintaining normal vascular homeostasis and is viewed as
atheroprotective. Therefore, functionally important variants of the
eNOS gene could influence individual susceptibility to
atherosclerosis by altering the amount of NO generated by the
endothelium.
A common variant of the eNOS gene that modifies its coding
sequence (Glu298Asp) has been recently shown to produce an
enhanced susceptibility to intracellular proteolytic cleavage of the
eNOS Asp298. Another polymorphism in the promoter region of the
eNOS gene (T786C) has been recently associated with coronary
spasm by affecting eNOS expression. Therefore, the aim of the
present study was to investigate the relationship of the eNOS
Glu298Asp and T786C polymorphisms to the presence and severity
of CAD in the Italian population.
We found that both eNOS variants were significantly associated with
the occurrence of CAD in our population. Indeed, eNOS Asp/Asp and
CC genotypes conferred an increased risk of CAD, independently
from the other common risk factors (Table 1). Moreover,
simultaneously carriers of both Asp/Asp and at least one C allele
were at higher risk of CAD than carriers of single genotypes,
suggesting the possibility of an interactive effect between the
Glu298Asp and T786C polymorphisms of the eNOS gene on CAD
risk. Moreover, this potential interaction was also evident when we
evaluated the effects of the eNOS genetic variants on the severity of
CAD, estimated by means of the Duke scoring system, a prognostic
index that considers not only the number of stenosed vessels, but
also the percent narrowing of the major vessels and the anatomical
localization of the stenosis. As shown in Figure 1, the severity of CAD
was significantly associated with the presence of both Asp/Asp and
at least one C allele of the eNOS gene Glu298Asp and T786C
polymorphisms, respectively.
In conclusion, we provided evidence that the Glu298Asp and T786C
polymorphisms of the eNOS gene are associated with the presence,
extent and severity of angiographically assessed CAD in the Italian
population, raising the possibility of genotype-prevention strategies.
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