Nitric Oxide Synthase Genes

Because of the complex and multiorgan origin of hypertension, the genetic approach is the preferred strategy for discovering genes predisposing to the disease, a strategy that was successful mostly for monogenic forms of the disease. Both linkage studies in families with informative markers and case-control studies with biallelic markers or putative functional variants on candidate genes were widely used.Two studies published in this issue illustrate the interest and the limits of this approach on 2 genes responsible for the enzymatic generation of nitric oxide (NO).1 2 Among the multiple actions of NO, those involving the cardiovascular system were extensively documented and designate the genes coding for NO-generating enzymes as candidate genes.3 Because, in the mammalian genome, 3 genes encoding 3 different nitric oxide synthases (NOS) are responsible for enzymatic generation of NO from l-arginine in various cells and under various stimuli, the role of each gene in NO generation defines its place as a candidate gene in hypertension.Transgenic experiments supply the best arguments that the endothelial NOS (eNOS) is a strong candidate since pharmacological inhibition of this isoform is not available. Homozygous mice for the knockout of the eNOS gene have a level of blood pressure ≈15 mm Hg higher than control mice, a result obtained independently by 2 groups.4 5 More recently, the mouse eNOS cDNA was transduced in mice under the transcriptional control of a heterologous endothelial cell–targeting promoter, the preproendothelin gene promoter.6 Basal systolic and diastolic blood pressure were both reduced by ≈20 mm Hg in male transgenic mice overexpressing eNOS , owing to the presence of several copies of this chimeric gene in the genome of transgenic mice. Although this experiment is …