Ubiquitin proteasome system role in diabetic induced Heart Failure

Background:

Ubiquitin-mediated proteolysis of proteins plays a key role in the regulation of numerous cellular processes in the body; deviations in the Ubiquitin Proteasome System (UPS) function underlie the pathogenesis of various diseases. We aimed to decipher the association between UPS function in the heart of Type 2 diabetes (T2D) mice and Heart Failure (HF).

Methods:

A T2D model of db/db knock-out mice was established, and was further challenged with Angiotensin II (AngII). UPS role was studied in both the pre-diabetic and the diabetic phase of db/db mice using RNA Sequencing, qRT-PCR and Western Blot (WB) analysis.

Neonatal rat ventricular myocytes (NRVM) and Cardiac Fibroblast`s (CF) cell culture were used to further evaluate UPS function under diabetic conditions using qRT-PCR and WB analysis.

Results:

A reduction of 20S Proteasome Beta sub units: PSMB8, PSMB9 and Deubiquitinating enzymes family (DUB) member: USP18 were seen in diabetic mice. Ang II induction of HF in diabetic mice has led to an up-regulation in the DUB and E3 ligase genes (Uchl1 and Neurl1a respectively).

Furthermore; NRVM and CF exhibited a different distribution of free Ubiquitin and conjugated Ubiquitin.

Conclusions:

Diabetic mice exhibit a unique UPS gene profile compared to non-diabetic mice. Additionally, different UPS genes are altered once the diabetic mice are challenged with AngII. The detected genes are part of an E3 ligase and DUB families or components of the 20S proteasome; all are considered as vital for a well-functioning UPS.

Different free and conjugated Ubiquitin distribution were detected in both NRVM and CF pointing on diverse mechanism of UPS presented under diabetic conditions. Hence; our findings imply on the involvement of UPS in the diabetic state. Future experiments should address the possibility of manipulating the UPS in the heart and changing the cardiovascular effects of T2D.