Ubiquitin Proteasome System (UPS) role in diabetes-induced cardiomyopathy - The 68th Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery

Ortal Nahum-Ankonina ^1,2 Efrat Kurtzwald-Josefson ¹ Aaron Ciechanover ³ Maayan Waldman ^1,2 Orna Shwartz-Rohaker ¹ Edith Hochhauser ^1,2 Sam Meyer ¹ Dan Aravot ^1,2 Moshe Phillip ^2,4 Yaron D. Barac ^1,2

¹The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Israel
²Sackler Faculty of Medicine, Tel Aviv University, Israel
³Unit of Biochemistry, Faculty of Medicine, Technion-Israel Institute of Technology, Israel
⁴The Division of Endocrinology, Schneider Medical Center, Israel

Introduction: The ubiquitin proteasome system (UPS) plays a key role in regulating cellular processes in the body by driving proteolysis of damaged proteins. Deviations in the UPS underlie the pathogenesis of various diseases. This work aimed to identify associations between UPS and early cardiac modifications in a type 2 diabetes mellitus (T2DM) mouse model.

Methods: Heart tissues of both 6-(pre-diabetic) and 12-week-old (diabetic) db/db and WT mice were compared using RNA sequencing, qRT-PCR and protein expression analysis.

Results: Differences in cardiomyopathy-related gene expression such as Brain natriuretic peptide (BNP) and β-myosin heavy chain (MyH7) were found in db/db mice compared with WT mice. BNP encoded by the nppb gene is released in response to increased wall stress and is considered a heart failure biomarker, was significantly down-regulated in diabetic mice compared with WT mice. However, mRNA level of Myh7, a muscle component involved in contractility and functionality was upregulated in db/db mice. In parallel, expression of specific UPS-related genes was downregulated in db/db mice compared with WT, including genes encoding the 20S inducible proteasome beta subunits PSMB8, PSMB9 and their respective proteins LMP7 and LMP2. Additionally, expression of the USP18 gene, a deubiquitinating enzyme, was reduced in db/db mice compared with WT. mRNA levels of RNF167, encoding an E3 ligase involved in regulating lysosomal exocytosis, were increased in pre-diabetic and diabetic mice, and corresponding protein levels were significantly increased in diabetic mice compared with WT.

Conclusions: These findings suggest specific alterations in expression of UPS-related genes that are essential to the system’s function in diabetic mice, including altered levels of proteasome components, E3 ligases, and deubiquitinating enzymes. Future studies investigating the correlation between the UPS genes and proteins alterations and T2DM progression will enhance our understanding of the impaired cellular protein homeostasis underlying diabetic cardiomyopathy.