THE ROLE OF SIK2 IN MEDIATING CARDIAC PATHOLOGICAL REMODELLING

Student thesis: Phd

Abstract

Heart failure (HF) is a complex pathology, characterized by an impaired ability of the heart in pumping blood in the body. One of the principal causes of HF development is myocardial infarction (MI), which determines the beginning of adverse tissue remodelling characterised by fibrosis, hypertrophy and cell death. Due to the limited capacity of cardiomyocytes to proliferate, this damage is permanent and progresses, leading eventually to the death of the patient. Current available treatments are unable to stop the progression of the remodelling. For this reason, the identification of new targets for therapeutic approaches is necessary. Recently, the possibility of promoting the proliferation of resident cardiomyocytes has been proposed by regenerative medicine. The modulation of specific signalling pathways, such as Hippo and AKT, has demonstrated promising results in improving post-MI HF progression. This study aims to investigate the role of Salt-inducible kinase 2 (SIK2) as a new potential modulator of cardiomyocyte proliferation after MI. A combination of in vivo and in vitro experiments dissected the unknown role of SIK2 in cardiac cells. In vitro experiments were conducted in neonatal rat cardiomyocytes (NRCMs) using an adenovirus-mediated overexpression system and a new inhibitor of SIK2 activity, ARN-3236. For in vivo experiments, a global SIK2 knockout (SIK2-/-) mouse model underwent myocardial infarction and animals were monitored for 4 weeks. We demonstrated that SIK2 is differentially expressed according to developmental stages in cardiac tissue and that its expression increases during HF progression. Initially, we performed in silico analysis of reported SIK2 interactors to determine the possible mechanisms of action of this kinase, which identified that SIK2 activity could be related to the Hippo and AKT pathways. In vitro experiments confirmed this finding. In NRCMs, overexpression of SIK2 promotes activation of the Hippo and PI3K-AKT pathways, increasing the phosphorylation of LATS and AKT, respectively. Adenoviral-mediated SIK2 overexpression results in the enlargement of cell area and production of BNP, both of which indicate the development of a hypertrophic phenotype. These effects were attenuated after SIK2 inhibition via ARN-3236. In vivo data have further confirmed the role of SIK2 in cardiac pathology. After MI, SIK2-/- mice exhibited a better survival outcome and dramatically smaller scar than wild type counterparts. This suggested that lack of SIK2 has a protective effect after MI. In conclusion, in vitro and in vivo data identified an important role of SIK2 in cardiomyocytes, potentially through the modulation of both Hippo and AKT pathway, proposing SIK2 as a potential new target for HF treatment.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorElizabeth Cartwright (Supervisor), Xin Wang (Supervisor) & Delvac Oceandy (Supervisor)

Keywords

  • heart failure
  • Salt-inducible kinase 2

Cite this

'