Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase

Circulation. 2003 Jul 1;107(25):3152-8. doi: 10.1161/01.CIR.0000074229.93804.5C. Epub 2003 Jun 16.


Background: In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD.

Methods and results: In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser1177, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56+/-8% (from +48+/-8% at beginning to +104+/-11% after 4 weeks, P<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0+/-0.7 versus C 0.5+/-0.3 arbitrary units, P<0.05) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium (1.2+/-0.9 versus 0.3+/-0.2 arbitrary units, P<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (R=0.80, P<0.05) and between phospho-eNOS and Delta APV (R=0.59, P<0.05).

Conclusions: Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Akt-dependent phosphorylation of eNOS on Ser1177.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine
  • Aged
  • Blood Flow Velocity / drug effects
  • Blood Flow Velocity / physiology
  • Coronary Artery Bypass
  • Coronary Artery Disease / enzymology
  • Coronary Artery Disease / physiopathology*
  • Coronary Artery Disease / surgery
  • Coronary Circulation
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / physiopathology*
  • Follow-Up Studies
  • Humans
  • Male
  • Mammary Arteries / enzymology
  • Mammary Arteries / physiology
  • Mammary Arteries / physiopathology
  • Middle Aged
  • Motor Activity* / physiology
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type III
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Reference Values
  • Stress, Mechanical
  • Treatment Outcome
  • Vasodilation / physiology


  • Proto-Oncogene Proteins
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Acetylcholine