Promoter and Exon 7 Polymorphism of Endothelial Nitric Oxide Synthase: Impact on Endothelial Function and Its Correction by Exercise Trainin
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《动脉硬化血栓血管生物学》
Heart Center Department of Internal Medicine/Cardiology, University of Leipzig, Struempellstrasse, Leipzig, Germany
To the Editor:
In a recently published article in Arteriosclerosis, Thrombosis, and Vascular Biology, we assessed the impact of the promoter (T-786C) and exon 7 (G894T) polymorphism of the eNOS gene on endothelial function and endothelial response to physical exercise training in patients with coronary artery disease (CAD).1 We were able to demonstrate, with a statistical power of 85%, that patients with CAD who were positive for the promoter (T-786C) or the exon 7 (G894T) polymorphism showed an impaired acetylcholine-mediated increase in blood flow average peak velocity compared with those with wild-type variants.1
We point out that our study population consisted of carefully selected patients with CAD with a preserved left ventricular function who are suitable for a training program. The promoter polymorphism (T-786C) was shown to be associated with the occurrence of myocardial infarction and consequently reduced left ventricular function.2 Because patients with an impairment of left ventricle function were excluded from study participation, this might explain why patients homozygous for the promoter polymorphism (T-786C) are underrepresented in our study population.1 However, we did not exclude patients with myocardial infarction who had a global normal left ventricular function but local wall motion irregularities. Moreover, Nakayama et al clearly emphasized that the T-786C mutation is a feature of patients having an acute myocardial infraction caused by coronary vasospasm in the absence of a significant CAD.2 In contrast, only 1 of 329 patients with stenosed coronary arteries was homozygous for the promoter polymorphism in their study,2 which is in accordance with our data.1 Nevertheless, the allele frequencies of the Asp298 variant in our study are comparable to those of a recently published clinical trial involving 1850 white subjects.3
We appreciate that Drs Maiolino and Rossi emphasized that there is much debate about the functional consequences of the exon 7 polymorphism (G894T). We are aware of Fairchild’s study proving that acidic hydrolysis represents a mechanism for cleavage of the Glu298-Asp variant of eNOS.4 However, the interpretation that this study, which also represents an artificial in vitro system, excludes all possibilities of a functional significance of the exon 7 polymorphism (G894T) in vivo seems to be a jumped-to conclusion. Numerous clinical trials are supporting the hypothesis of a physiological relevance of this polymorphism in vivo. One important study clearly revealed reduced eNOS activity in renal artery specimen from T allele carriers.5 Moreover, the concept of a functional significance of this polymorphism is supported by an impaired platelet-derived NO release from healthy individuals harboring the exon 7 mutation (G894T).6 These results are in accord with a recently published clinical trial involving 1850 patients with CAD.3 It was shown that patients homozygous for the exon 7 polymorphism (G894T) had a higher risk for a major clinical cardiovascular event within 1 year after coronary stent implantation.3 The knowledge about the physiological consequences on the endothelial level was further extended by Leeson et al.7 They demonstrated an impairment of flow-mediated vasodilatation of the forearm in healthy young adults with the exon 7 polymorphism (G894T) in the presence of the environmental co-factor smoking.7
Overall, our data do support the hypothesis that endothelial function in response to acetylcholine is impaired not only in promoter polymorphism (T-786C)-positive patients but also in patients with the exon 7 mutation (G894T).1 Moreover, 4 weeks of physical exercise training resulted in a blunted endothelium-dependent increase in average peak velocity only in promoter polymorphism (T-786C)-positive patients but not in exon 7 (G894T) and wild-type allele carriers.1 As it was acknowledged by Rossi and Maiolino, this finding might partially explain why some patients with CAD respond better to an exercise training intervention than do others.8
References
Erbs S, Baither Y, Linke A, Adams V, Shu Y, Lenk K, Gielen S, Dilz R, Schuler G, Hambrecht R. Promoter but Not Exon 7 Polymorphism of Endothelial Nitric Oxide Synthase Affects Training-Induced Correction of Endothelial Dysfunction. Arterioscler Thromb Vasc Biol. 2003; 23: 1814–1819.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Ogawa H, Kugiyama K, Mizuno Y, Harada E, Nakamura S, Ito T, Saito Y, Miyamoto Y, Ogawa Y, Nakao K. T-786C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. Am J Cardiol. 2000; 86: 626–634.
Gorchakova O, Koch W, von Beckerrath N, Mehilli J, Sch?mig A, Kastrati A. Association of a genetic variant of endothelial nitric oxide synthase within the 1 year clinical outcome after coronary stent placement. Eur Heart J. 2003; 24: 820–827
Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ, Sessa WC. Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)–>Asp variant of human endothelial nitric-oxide synthase. J Biol Chem. 2001; 276: 26674–26679.
Persu A, Stoenoiu MS, Messiaen T, et al. Modifier effects of eNOS in autosomal dominant polycystic kidney disease. Hum Mol Genet. 2002; 11: 229–241
Tanus-Santos JE, Desai M, Deak LR, Pezzullo JC, Abernethy DR, Flockhart DA, Freeman JE. Effects of endothelial nitric oxides synthase gene polymorphisms on platelet function, nitric oxide release, and interaction with estradiol. Pharmacogenetics. 2002; 13: 407–413
Leeson CP, Hingorani AD, Mullen MJ, Jeerooburkhan N, Kattenhorn M, Cole TJ, Muller DP, Lucas A, Humphries SE, Deanfield JE. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res. 2002; 90: 1153–1158.
Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of Exercise on Coronary Endothelial Function in Patients with Coronary Artery Disease. N Engl J Med. 2000; 342: 454–460.(Sandra Erbs; Axel Linke; )
To the Editor:
In a recently published article in Arteriosclerosis, Thrombosis, and Vascular Biology, we assessed the impact of the promoter (T-786C) and exon 7 (G894T) polymorphism of the eNOS gene on endothelial function and endothelial response to physical exercise training in patients with coronary artery disease (CAD).1 We were able to demonstrate, with a statistical power of 85%, that patients with CAD who were positive for the promoter (T-786C) or the exon 7 (G894T) polymorphism showed an impaired acetylcholine-mediated increase in blood flow average peak velocity compared with those with wild-type variants.1
We point out that our study population consisted of carefully selected patients with CAD with a preserved left ventricular function who are suitable for a training program. The promoter polymorphism (T-786C) was shown to be associated with the occurrence of myocardial infarction and consequently reduced left ventricular function.2 Because patients with an impairment of left ventricle function were excluded from study participation, this might explain why patients homozygous for the promoter polymorphism (T-786C) are underrepresented in our study population.1 However, we did not exclude patients with myocardial infarction who had a global normal left ventricular function but local wall motion irregularities. Moreover, Nakayama et al clearly emphasized that the T-786C mutation is a feature of patients having an acute myocardial infraction caused by coronary vasospasm in the absence of a significant CAD.2 In contrast, only 1 of 329 patients with stenosed coronary arteries was homozygous for the promoter polymorphism in their study,2 which is in accordance with our data.1 Nevertheless, the allele frequencies of the Asp298 variant in our study are comparable to those of a recently published clinical trial involving 1850 white subjects.3
We appreciate that Drs Maiolino and Rossi emphasized that there is much debate about the functional consequences of the exon 7 polymorphism (G894T). We are aware of Fairchild’s study proving that acidic hydrolysis represents a mechanism for cleavage of the Glu298-Asp variant of eNOS.4 However, the interpretation that this study, which also represents an artificial in vitro system, excludes all possibilities of a functional significance of the exon 7 polymorphism (G894T) in vivo seems to be a jumped-to conclusion. Numerous clinical trials are supporting the hypothesis of a physiological relevance of this polymorphism in vivo. One important study clearly revealed reduced eNOS activity in renal artery specimen from T allele carriers.5 Moreover, the concept of a functional significance of this polymorphism is supported by an impaired platelet-derived NO release from healthy individuals harboring the exon 7 mutation (G894T).6 These results are in accord with a recently published clinical trial involving 1850 patients with CAD.3 It was shown that patients homozygous for the exon 7 polymorphism (G894T) had a higher risk for a major clinical cardiovascular event within 1 year after coronary stent implantation.3 The knowledge about the physiological consequences on the endothelial level was further extended by Leeson et al.7 They demonstrated an impairment of flow-mediated vasodilatation of the forearm in healthy young adults with the exon 7 polymorphism (G894T) in the presence of the environmental co-factor smoking.7
Overall, our data do support the hypothesis that endothelial function in response to acetylcholine is impaired not only in promoter polymorphism (T-786C)-positive patients but also in patients with the exon 7 mutation (G894T).1 Moreover, 4 weeks of physical exercise training resulted in a blunted endothelium-dependent increase in average peak velocity only in promoter polymorphism (T-786C)-positive patients but not in exon 7 (G894T) and wild-type allele carriers.1 As it was acknowledged by Rossi and Maiolino, this finding might partially explain why some patients with CAD respond better to an exercise training intervention than do others.8
References
Erbs S, Baither Y, Linke A, Adams V, Shu Y, Lenk K, Gielen S, Dilz R, Schuler G, Hambrecht R. Promoter but Not Exon 7 Polymorphism of Endothelial Nitric Oxide Synthase Affects Training-Induced Correction of Endothelial Dysfunction. Arterioscler Thromb Vasc Biol. 2003; 23: 1814–1819.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Ogawa H, Kugiyama K, Mizuno Y, Harada E, Nakamura S, Ito T, Saito Y, Miyamoto Y, Ogawa Y, Nakao K. T-786C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. Am J Cardiol. 2000; 86: 626–634.
Gorchakova O, Koch W, von Beckerrath N, Mehilli J, Sch?mig A, Kastrati A. Association of a genetic variant of endothelial nitric oxide synthase within the 1 year clinical outcome after coronary stent placement. Eur Heart J. 2003; 24: 820–827
Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ, Sessa WC. Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)–>Asp variant of human endothelial nitric-oxide synthase. J Biol Chem. 2001; 276: 26674–26679.
Persu A, Stoenoiu MS, Messiaen T, et al. Modifier effects of eNOS in autosomal dominant polycystic kidney disease. Hum Mol Genet. 2002; 11: 229–241
Tanus-Santos JE, Desai M, Deak LR, Pezzullo JC, Abernethy DR, Flockhart DA, Freeman JE. Effects of endothelial nitric oxides synthase gene polymorphisms on platelet function, nitric oxide release, and interaction with estradiol. Pharmacogenetics. 2002; 13: 407–413
Leeson CP, Hingorani AD, Mullen MJ, Jeerooburkhan N, Kattenhorn M, Cole TJ, Muller DP, Lucas A, Humphries SE, Deanfield JE. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res. 2002; 90: 1153–1158.
Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of Exercise on Coronary Endothelial Function in Patients with Coronary Artery Disease. N Engl J Med. 2000; 342: 454–460.(Sandra Erbs; Axel Linke; )