Mst1/2 Kinases Inhibitor, XMU-MP-1, Attenuates Angiotensin II-Induced Ascending Aortic Expansion in Hypercholesterolemic Mice

Abstract

Background: Ascending and abdominal aortic aneurysms (AAs) are asymptomatic, permanent dilations of the aorta with surgical intervention as the currently available therapy. Hippo-Yap signaling cascade plays a critical role in stem cell self-renewal, tissue regeneration and organ size control. By using XMU-MP-1, a pharmacological inhibitor of the key component of Hippo-Yap signaling, MST1/2, we examined the functional contribution of Hippo-Yap in the development of AAs in Angiotensin II (AngII)-infused hypercholesterolemic mice.Methods and Results: MST, p-MST, p-YAP, p-MOB and TAZ proteins in AngII-infused ascending and abdominal aortas were assessed by immunohistochemical and western blot analyses. To examine the effect of MST1/2 inhibition on AAs, western diet-fed low density lipoprotein (LDL) receptor −/− mice infused with AngII were administered with either vehicle or XMU-MP-1 for 5 weeks. Hippo-YAP signaling proteins were significantly elevated in AngII infused ascending and abdominal aortas. XMU-MP-1 administration resulted in the attenuation of AngII-induced ascending AAs without influencing abdominal AAs and aortic atherosclerosis. Inhibition of Hippo-YAP signaling also resulted in the suppression of AngII-induced matrix metalloproteinase 2 (MMP2) activity, macrophage accumulation, aortic medial hypertrophy and elastin breaks in the ascending aorta. Conclusions:The present study demonstrates a pivotal role for the Hippo-YAP signaling pathway in AngII-induced ascending AA development.

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

“…XMU-MP-1 is the chemical probe widely being used to study the Hippo pathway. Several publications have described the cellular roles of MST1/2 in the Hippo pathway with XMU-MP-1, assuming the molecule can pharmacologically inhibit the function of MST1/2 [54,[57][58][59][60][61][62][63].…”

The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response

“…Recently, Jones et al showed that JCAD (Junctional Cadherin 5 Associated) regulates adhesion molecule expression and monocyte-EC adhesion by interacting with LATS2, which is a kinase in the Hippo pathway, in a LATS2dependent manner (152). However, the administration of an inhibitor of the Hippo kinase MST1/2 resulted in the attenuation of Angiotensin II-induced ascending arterial aneurysms without affecting aortic atherosclerotic plaque progression (158). Due to mouse models and the effects of exogenous inhibition, further direct investigation of the role of Hippo kinase in atherosclerosis is needed.…”