CORRESPONDENCE: LETTER TO THE EDITOR
Effects of Endothelial Nitric Oxide Synthase Gene Polymorphisms on Oxidative Stress, Inflammatory Status, and Coronary Atherosclerosis: An Example of a Transient Phenotype
Charalambos Antoniades, MD*,
Dimitris Tousoulis, MD, PhD, FACC and
Christodoulos Stefanadis, MD, FACC, FESC
* Athens University Medical School, Hippokration Hospital, Vasilissis Sophias 114, 115 28 Athens, Greece (Email: antoniades{at}panafonet.gr).
In their recent study, Rossi et al. (1) showed that the T786C polymorphism on the promoter region of the endothelial nitric oxide synthase (eNOS) gene modifies redox-sensitive inflammatory pathways, and may be a predictor for clinical outcome in high-risk patients with coronary atherosclerosis. Although this polymorphism was found to be in linkage disequilibrium with the functional polymorphism G894T (D' = 0.3), the latter had no predictive value in this cohort, despite the results of a large meta-analysis suggesting the opposite (2). However, the observation that the 894T/786T haplotype leads to a worse cardiovascular death-free survival supports the hypothesis of a more complex association between these polymorphisms and eNOS function.
We have recently shown (3) that the presence of the 894T allele is associated with higher levels of oxidized low-density lipoprotein and proinflammatory cytokines only under conditions of "biological stress," such as during the acute phase of myocardial infarction, an effect not observed in the same subjects 1 year after the event, or in healthy individuals. Moreover, the 894T allele seems to be associated with impaired endothelial function in high-risk patients (4) and in healthy smokers (5), but not in healthy, low-risk individuals (5).
In the present study, Rossi et al. (1) actually introduce the hypothesis that the previously observed transient effect of the 894T allele on oxidative stress, inflammatory process, and endothelial function (3–5) could actually be due to its linkage disequilibrium with the 786T allele (which has been suggested to modify eNOS expression). However, this could be due to the complex interaction of both polymorphisms constituting the 894T/786T haplotype. The combination of low eNOS expression (induced by the 786T allele) and increased susceptibility of eNOS to proteolytic cleavage (induced by the 894T allele) (6) could lead to a combined effect on the associated phenotype of nitric oxide bioavailability, and the subsequent alterations of oxidative stress and inflammatory status. Therefore, further molecular studies are required to explore the transient behavior of eNOS genotypes/haplotypes, leading to a different phenotype, depending on the underlying disease state.
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- Rossi GP, Maiolino G, Zanchetta M, et al. The T(–786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients J Am Coll Cardiol 2006;48:1166-1174.[Abstract/Free Full Text]
- Casas JP, Bautista LE, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23,028 subjects Circulation 2004;109:1359-1365.[Abstract/Free Full Text]
- Antoniades C, Tousoulis D, Vasiliadou C, et al. Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction J Am Coll Cardiol 2005;46:1101-1109.[Abstract/Free Full Text]
- Antoniades C, Tousoulis D, Vasiliadou C, et al. Genetic polymorphism G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors Int J Cardiol 2006;107:95-100.[CrossRef][ISI][Medline]
- Leeson CP, Hingorani AD, Mullen MJ, et al. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function Circ Res 2002;90:1153-1158.[Abstract/Free Full Text]
- Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298 Proc Natl Acad Sci U S A 2000;97:2832-2835.[Abstract/Free Full Text]
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