The Hippo pathway plays an important role in the regulation of cell proliferation, apoptosis, and differentiation, making it a potential therapeutic target for many diseases. Inhibition of the Hippo pathway may lead to the induction of cell proliferation and tissue regeneration, which could be beneficial in several pathological conditions, including cardiovascular diseases. Mst1 and Mst2 are two major components of the Hippo pathway that can potentially be targeted pharmacologically since they can interact with many ligands, including chemical compounds. Genetic inhibition of Mst1 and Mst2 is associated with improvement of cardiac remodelling following pathological stimuli. However, studies on evaluating the effects of Mst1/2 pharmacological inhibition in treating cardiovascular diseases are limited. This study aimed to investigate the effects of Mst1/2 pharmacological inhibition in the cardiovascular system in pathological settings. This study comprises in vitro studies using neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs) and in vivo experiments using mouse models of pressure overload hypertrophy and myocardial infarction. The effects of the Mst1/2 inhibitor (XMU-MP-1) were examined in both in vitro and in vivo systems. In addition, analysis of a novel Mst2-specific inhibitor (MRT137) was conducted in an in vitro model using NRCMs. XMU-MP-1 significantly increased YAP activity in NRCM and HUVEC cultures. In NRCM, XMU-MP-1 was found to protect against phenylephrine-induced hypertrophy and peroxide-induced apoptosis. Additionally, XMU-MP-1 was able to induce NRCM proliferation. However, XMU-MP-1 appeared to reduce cell viability and angiogenesis in HUVECs. The in vivo experiments using C57Bl/6 mice showed that XMU-MP-1 treatment preserved cardiac function, prevented cardiac hypertrophy and reduced fibrosis following transverse aortic constriction (TAC). However, XMU-MP-1 treatment did not show any significant effects in terms of survival, cardiac function and remodelling in mouse models of acute and sub-acute myocardial infarction (MI). In addition, in vitro experiments using NRCM culture to study the effects of a novel Mst2 inhibitor, MRT137, revealed that YAP activity was augmented, accompanied by increased proliferation and reductions in NRCM apoptosis and hypertrophy. In conclusion, inhibition of Mst1 and Mst2 using pharmacological compounds is protective against pressure overload cardiac remodelling, possibly via protection against cardiomyocyte hypertrophy and apoptosis. However, Mst1/2 inhibition does not affect the cardiac phenotype following MI. This study provides new insights into the possibility of targeting Mst1/2 for pharmacological treatment of pathological cardiac hypertrophy in the future.
|Date of Award||1 Aug 2021|
- The University of Manchester
|Supervisor||Delvac Oceandy (Supervisor) & Sabu Abraham (Supervisor)|
- Cardiovascular system
- The Hippo pathway