Article Text
Abstract
Introduction Heart failure (HF) is characterised by an inadequate cardiac pumping ability and is one of the major causes of death worldwide. Numerous conditions lead to HF, such as myocardial infarction (MI). After MI, an extensive death of cardiac cells combined with limited regenerative capacity causes a pathological remodelling of the left ventricle, characterized by substantial fibrosis and hypertrophy. Replacement of damaged tissue or limitation of pathological progression are not achievable with current treatments. Thus, novel therapeutic approaches to address this unmet medical need are still required.
We decided to explore the unknown role of Salt-inducible kinase 2 (SIK2) in cardiac cells to potentially identify a novel target for HF therapy. Recently, this kinase has been identified as a key modulator of Hippo pathway-mediated stimulation of cell proliferation in Drosophila and a putative mediator of cardiac hypertrophy progression in response to chronic high-salt intake.
Methods and Results Firstly, we demonstrated that SIK2 protein is expressed in both fibroblasts and cardiomyocytes. We also identified a variation of its expression during the different developmental stages of the organism, displaying a greater level during the neonatal phase, and an elevated expression during HF progression, underlining the decisive importance of this kinase in myocardial tissue organization and remodelling.
We performed an in-silico analysis to unroll the mediators of this effect, which suggested that SIK2 activity is mainly mediated by either Hippo or Akt pathway. Exploiting an adenovirus overexpression system, we observed evidence of increased Akt phosphorylation levels. We also found that SIK2 overexpression in primary neonatal rat cardiomyocytes causes activation of LATS, one of the main components of the Hippo pathway, suggesting a potential SIK2-mediated regulation of the Hippo pathway. These alterations did not cause changes in survival rate or cell proliferation. However, it clearly promoted the induction of cell hypertrophy.
Conclusion In summary, these preliminary data suggest that SIK2 might modulate the hypertrophic response of cardiac tissue during pathological insults.
Conflict of Interest No