The scientists at University of Michigan Medical Center, Ann Arbor, MI published on a new application of hydroxypropyl beta-cyclodextrin (HPβCD) as drug.
Studying the cellular mechanism of abdominal aortic aneurysm (AAA), a severe aortic disease with a high mortality rate. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Prof. Fan’s group investigated the role of transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis.
The expression of TFEB was measured in human and mouse aortic aneurysm samples. Vascular smooth muscle cell (VSMC)-selective Tfeb knockout mice and different mouse AAA models were used.
It was found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2 (BCL2). BCL2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. Consistently, it was observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, it was demonstrated that HPβCD activates TFEB and inhibits AAA formation and progression in mice. HPβCD also inhibits AAA in a VSMC TFEB-dependent manner in mouse models. TFEB knockdown abolished the anti-apoptotic effect of HPβCD, indicating an essential role of TFEB in the HPβCD-dependent inhibition of apoptosis. The effect of HPβCD is realized through reduction of intracellular cholesterol.
Mice were treated with HPβCD after the AAA had been established, the diameter of the suprarenal aorta (where most of the aneurysms occur in this model) was reduced and HPβCD significantly inhibited AAA progression.
The authors of the paper in Circulation concluded that TFEB protects against VSMC apoptosis and AAA. TFEB activation by HPβCD may be a promising therapeutic strategy for the prevention and treatment of AAA.
Fig. 1 demonstrates the proposed model for TFEB as a therapeutic target in AAA.
Lu, H., Sun, J., Liang, W., Chang, Z., Rom, O., Zhao, Y., … Fan, Y. (2020). Cyclodextrin Prevents Abdominal Aortic Aneurysm via Activation of Vascular Smooth Muscle Cell TFEB. Circulation. doi:10.1161/circulationaha.119.044803