Exercise Training in Patients with Chronic Heart Failure Promotes Restoration of High-Density Lipoprotein Functional Properties

Rationale: High-density lipoprotein (HDL) exerts endothelial-protective effects via stimulation of endothelial cell (EC) nitric oxide (NO) production. This function is impaired in patients with cardiovascular disease. Protective effects of exercise training (ET) on endothelial function have been demonstrated. Objective: This study was performed to evaluate the impact of ET on HDL-mediated protective effects and the respective molecular pathways in patients with chronic heart failure (CHF). Methods and Results: HDL was isolated from 16 healthy controls (HDL healthy ) and 16 patients with CHF-NYHA-III (HDL NYHA-IIIb ) before and after ET, as well as from 8 patients with CHF-NYHA-II (HDL NYHA-II ). ECs were incubated with HDL, and phosphorylation of eNOS-Ser 1177 , eNOS-Thr 495 , PKC-βII-Ser 660 , and p70S6K-Ser 411 was evaluated. HDL-bound malondialdehyde and HDL-induced NO production by EC were quantified. Endothelial function was assessed by flow-mediated dilatation. The proteome of HDL particles was profiled by shotgun LC-MS/MS. Incubation of EC with HDL NYHA-IIIb triggered a lower stimulation of phosphorylation at eNOS-Ser 1177 and a higher phosphorylation at eNOS-Thr 495 when compared with HDL healthy . This was associated with lower NO production of EC. In addition, an elevated activation of p70S6K, PKC-βII by HDL NYHA-IIIb , and a higher amount of malondialdehyde bound to HDL NYHA-IIIb compared with HDL healthy was measured. In healthy individuals, ET had no effect on HDL function, whereas ET of CHF-NYHA-IIIb significantly improved HDL function. A correlation between changes in HDL-induced NO production and flow-mediated dilatation improvement by ET was evident. Conclusions: These results demonstrate that HDL function is impaired in CHF and that ET improved the HDL-mediated vascular effects. This may be one mechanism how ET exerts beneficial effects in CHF.