Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice.
Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle (RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca(2+) removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.
Larsen
Karl-Otto
KO
Institute for Experimental Medical Research, Surgical Bldg., 4th floor, Ullevål Univ. Hospital, Kirkeveien 166, N-0407 Oslo, Norway. karlottl@medisin.uio.no
Sjaastad
Ivar
I
Svindland
Aud
A
Krobert
Kurt A
KA
Skjønsberg
Ole Henning
OH
Christensen
Geir
G
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003971:Diastole / Q000502:physiology; D004452:Echocardiography; D006439:Hemodynamics / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000502:physiology; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D011869:Radioligand Assay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology*; D018497:Ventricular Dysfunction, Right / Q000000981:diagnostic imaging / Q000503:physiopathology; D000099211:Phospholamban
D000262:Adenylyl Cyclases; D002135:Calcium-Binding Proteins; D000099211:Phospholamban