Is Atherosclerosis a No NO State?
To the Editor:
A recent article in Circulation by Lüscher’s group (Oemar et al)1 has reported that in tissue derived from human atherosclerotic lesions, endothelial NO synthase (eNOS) protein expression as well as NO release are markedly reduced. They then suggested that these reductions are involved in the progression of atherosclerosis.
We would like to provide further support for their contention that an altered NO system is involved in human atherosclerosis. In a series of articles, our group has established that patients with Bartter syndrome or Gitelman syndrome, syndromes that show a peculiar picture of vascular hyporeactivity characterized by normotension/hypotension in the presence of elevated levels of pressor agents (eg, angiotensin II, norepinephrine, and aldosterone), have an anomalous calcium-dependent signaling system2 and an upregulation of the NO system.3 4 In particular, this upregulation is characterized by increased ecNOS mRNA levels as well as increased and correlated urinary excretions of NO metabolites (NO2−/NO3−) and cGMP, the second messenger of NO. In these same patients, we have also demonstrated a reduced susceptibility of their LDL to oxidation,5 as shown by reduced production of thiobarbituric acid–reactive substances as well as volatile lipid peroxidation products such as pentanal and hexanal. In addition, the lag phase of conjugated diene formation in the Bartter and Gitelman patients was strongly correlated with urinary excretion of NO2−/NO3−. This suggests that NO serves as an antioxidant and therefore as a protective mechanism against oxidative stress, endothelial dysfunction, and atherosclerosis. Our results in Bartter and Gitelman patients therefore represent the mirror image of the results reported by Oemar et al1 and thus provide further support for and evidence of the importance of NO in the prevention of atherosclerosis and in related conditions such as hypertension, diabetes, and smoking.
- Copyright © 1999 by American Heart Association
Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Lüscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494–2498.
Calò L, D’Angelo A, Cantaro S, Bordin MC, Favaro S, Antonello A, Borsatti A. Increased urinary NO2−/NO3− and cyclic GMP levels in patients with Bartter’s syndrome: relationship to vascular reactivity. Am J Kidney Dis. 1996;27:874–879.
Calò L, Sartore G, Bassi A, Basso C, Bertocco S, Marin R, Zambon S, Cantaro S, D’Angelo A, Davis PA, Manzato E, Crepaldi G. Reduced susceptibility of low density lipoprotein to oxidation in patients with overproduction of nitric oxide (Bartter’s and Gitelman’s syndrome). J Hypertens. 1998;16:1001–1008.
We greatly appreciate the comments by Davis and Calò related to our recently published article.R1 The syndrome the authors studied, namely, Bartter and Gitelman patients, is of great interest in this context. The fact that NO serves as an antioxidant and therefore a protective mechanism against oxidative stress is also in line with our recently published “Current Perspective” in Circulation.R2 It is of great interest that nature has provided a mirror picture of atherosclerosis in these patients and that this mirror picture provides further support for the protective role of NO against atherosclerosis and related cardiovascular conditions.
Oemar BS, Tschudi MR, Godoy N, Brovkovich F, Malinski T, Lüscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494–2498.
Wever RMF, Lüscher TF, Cosentino F, Rabelink TJ. Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation. 1998;97:108–112.