The Ubiquitin Proteasome System as a Potential Target for Reverse Cardiac Remodeling in LVAD Patients - The 63rd Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery 12-13 April 2016, David Intercontinental Hotel, Tel-Aviv, Israel

Objectives: Heart failure (HF) is the leading hospitalization cause in the USA, usually following either dilated (DCM) or ischemic cardiomyopathy (ICM). Though the ubiquitin proteasome system (UPS) plays a central role in remodeling, little is known on its role in HF and cardiac remodeling. Therefore, the present study characterizes the UPS activity in human HF patients.

Methods: Left ventricular myocardial tissue of HF patients was collected at the time of left ventricular assist device implantation (LVAD). A patient cohort of n = 19 patients with ICM (age: 59.84 yrs 1.83, 100 % male) and n = 22 patients with DCM (age: 58.86 yrs 2.53, 73 % male) were assessed. Western blot was used to quantify ubiquitinated 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: ICM patients had a higher expression of poly- ubiquitinated 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 (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 UPS activity as observed by different patterns of E3 ligases and UPS activation markers. This preliminary understating of the UPS role in HF may affect future induction tools for reverse cardiac remodeling.