Regular Physical Activity Improves Endothelial Function in Patients With Coronary Artery Disease by Increasing Phosphorylation of Endothelial Nitric Oxide Synthase

TLDR

Exercise training improves arterial endothelial function in stable coronary artery disease, partly due to endothelial nitric oxide synthase (eNOS) activity, a key protective factor against atherosclerosis. The study aimed to assess how exercise training affects endothelial function and eNOS/Akt phosphorylation in the left internal mammary artery of stable CAD patients. In a 4‑week randomized comparison of 17 trained versus 18 control CAD patients, endothelium‑dependent vasodilation and peak flow velocity to acetylcholine were measured in the left internal mammary artery, and LIMA tissue was analyzed for eNOS, phospho‑eNOS‑Ser1177, Akt, and phospho‑Akt by Western blot and qRT‑PCR. Exercise training increased acetylcholine‑induced APV by 56%, doubled eNOS protein, quadrupled phospho‑eNOS‑Ser1177, and the rise in vasodilation correlated with Akt‑dependent eNOS phosphorylation, demonstrating improved endothelial function in stable CAD.

Abstract

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-Ser 1177 , 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 Ser 1177 -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 Δ 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 Ser 1177 .