NU 2022-216
INVENTORS
Hossein Ardehali*
Yuki Tatekoshi
SHORT DESCRIPTION
A small-molecule inhibitor for treating, preventing, and reversing heart failure with preserved ejection fraction (HFpEF).
ABSTRACT
HFpEF is a common cause of mortality worldwide, but the underlying pathophysiology is not well understood and treatment options are limited. Patients with HFpEF exhibit dysfunctional endothelial cells that line blood vessels, leading to a loss of vascular elasticity. Current hypertension medications, including Angiotensin II receptor blockers and sodium-glucose cotransporter-2 (SGLT2) inhibitors, are commonly used to treat patients suffering from HFpEF. However, these methods of treatment only increase quality of life and reduce hospitalizations; they do not decrease mortality rates.
A team of researchers at Northwestern University genetically engineered a mouse model that exhibit HFpEF. They found that Hexokinase-1 (HK1), a highly expressed protein in heart endothelial cells, dislocates from the mitochrondria in heart endothelial cells of the diseased animals. Dislocation of HK1 results in a reduction of protein N-glycosylation and an increase of O-linked-N-acetylglucosaminylation (O-GlcNAcylation), which ultimately leads to the defects in angiogenesis that are commonly observed in patients with HFpEF. Using 5S-GlcNHex, an inhibitor of the enzyme that catalyzes protein O-GlcNAcylation – O-GlcNAc transferase (OGT), the researchers observed that decreased protein O-GlcNAcylation reversed the HFpEF phenotype. These results indicate that our new pharmacological approach can be a viable therapy to prevent, treat, and reverse HFpEF. This technology offers a new mechanism for studying HFpEF and provides a new therapeutic strategy for an otherwise fatal condition.
APPLICATIONS
Prevention and treatment of HFpEF
ADVANTAGES
Offers novel therapeutic option for HFpEF
Can improve the lives of patients at risk of developing HFpEF
Can reduces mortality rates attributed to heart failure
PUBLICATION
Tatekoshi Y, Shapiro JS, Liu M, Bianco GM, Tatekoshi A, De Jesus A, Koleini N, Wasserstrom JA, Dillmann WH, Weinberg S, and Ardehali H (2022) Dislocation Of Hexokinase1 From Mitochondria Results In Heart Failure With Preserved Ejection Fraction Through Hyper O-glcnacylation In Endothelial Cells. Circulation Research. 131:AP3014
IP STATUS
A PCT application has been filed