The Ubiquitin Proteasome System in Dilated and Ischemic Cardiomyopathy: Is there a Potential Therapeutic Target?

Objective: Worldwide, more than 26 million people are living with heart failure (HF), one of the leading causes of hospitalization in the US. HF possibly occurs following dilated (DCM) or ischemic cardiomyopathy (ICM). Both forms of cardiomyopathy are associated with cardiac remodelling, where the ubiquitin proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. Therefore, the present study characterizes the UPS in human heart tissue in DCM and ICM patients.

Methods: Left ventricular myocardial tissue of patients with end-stage HF was collected at the time point of implantation of a ventricular assist device (VAD). A patient cohort of n = 19 patients with ICM (age: 59.84 years ± 1.83, 100% male) and n = 22 patients with DCM (age: 58.86 years ± 2.53, 73% male) were assessed. Western blot was used to quantify ubiquitinylated proteins, E3 ubiquitin ligases muscle atrophy F-box (MAFbx)/atrogin-1, muscle RING finger 1 (MuRF1) and eukaryotic translation initiation factor 4E (eIF4E). The peptidase activities (chymotrypsin-like and trypsin-like) of the proteasome were determined fluorometrically. Additionally, enzyme activity of NAD(P)H oxidase was detected as an index of reactive oxygen species (ROS) production.

Results: Compared with patients with DCM, patients with ICM had a higher expression of poly-ubiquitinylated proteins (ICM: 0.90 ± 0.06, DCM: 0.72 ± 0.05, p = 0.019) and MAFbx (ICM: 1.06 ± 0.08, DCM: 0.84 ± 0.05, p = 0.019). In contrast, trypsin-like peptidase activity of the proteasome was higher in patients with DCM compared with patients with ICM (DCM: 1.06 mU/mg ± 0.08, ICM: 0.78 mU/mg ± 0.11, p = 0.034). Interestingly, the chymotrypsin-like activity, the enzyme activity of the pro-oxidant source NAD(P)H oxidase as well as the expression of the translation factor eIF4E did not differ between ICM and DCM patients.

Conclusion: Myocardial tissue from patients suffering from DCM and ICM differ in protein expression and activity of the UPS. We observed different patterns of E3 ligases and UPS activation markers. This data suggests differing involvement of the UPS in the underlying pathologies. Further research is needed to investigate the role of the UPS as potential therapeutic target in patients with HF.