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1 Institute for Experimental Medical Research, Ulleval University Hospital, Oslo, Norway; Department of Pulmonary Medicine, Ulleval University Hospital, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway
2 Institute for Experimental Medical Research, Ulleval University Hospital, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway; Department of Cardiology, Ulleval University Hospital, Oslo, Norway
3 Department of Pathology, Aker University Hospital, Oslo, Norway
4 Department of Pharmacology, University of Oslo, Oslo, Norway
5 Department of Pulmonary Medicine, Ulleval University Hospital, Oslo, Norway
6 Institute for Experimental Medical Research, Ulleval University Hospital, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway
* To whom correspondence should be addressed. E-mail: karlottl{at}medisin.uio.no.
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 Ca2+ removal from cytosol during diastole. Mice exposed to 10 % oxygen for 1, 2 or 4 weeks were compared to controls. Cardiac hemodynamics was 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 weeks of hypoxia compared to controls (both P<0.05). In the RV and LV, 4 weeks 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 to 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 serine (Ser) 16 phosphorylated phospholamban (PLB) in the RV after 1, 2 and 4 weeks 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 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.
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