Activation of the ubiquitin proteolytic pathway in human septic heart and diaphragm.

Objective: Mechanisms of sepsis-induced myocardial and diaphragmatic alteration are multiple and remain largely unknown, particularly in humans. In the present study, we compared the inducible nitric oxide synthase (NOS-2) expression, the peroxynitrite production and the expression and activation of the ubiquitin proteolytic pathway in the wall of the 4 cardiac chambers, in the diaphragm, and in the rectus abdominis.

Patients: Seven patients who died from septic shock associated with a myocardial depression and 5 nonseptic (control) patients.

Measurements And Results: We evaluated protein expression by Western blot. Nitrotyrosin and ubiquitin residues were localized by immunofluorescence. NOS-2, nitrated proteins, free ubiquitin, and ubiquitinated proteins are overexpressed in the wall of the four cardiac cavities, in the diaphragm and in the rectus abdominis of septic patients at a similar level. Ubiquitinated proteins with a molecular mass of 50, 35, 30, and 25 kD were consistently detected in heart, diaphragm, and rectus abdominis of septic shock patients but lacking in nonseptic patients. In situ immunolabelling of ubiquitin showed a colocalisation with nitrotyrosine residues at the sarcomeric level of cardiac myocytes in septic patients.

Conclusions: This study showed the first evidence for the activation of the proteolytic ubiquitin-proteasome pathway in human heart and diaphragm in septic shock.