Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake.

Autor: Popov S; Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden., Takemori H; Laboratory of Cell Signaling and Metabolism, National Institute for Biomedical Innovation, Osaka, Japan., Tokudome T; Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan., Mao Y; Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan., Otani K; Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Research Institute, Osaka, Japan., Mochizuki N; Cell Biology, National Cerebral and Cardiovascular Research Institute, Osaka, Japan., Pires N; BIAL - Portela & Ca, S.A., S. Mamede do Coronado, Portugal., Pinho MJ; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal., Franco-Cereceda A; Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Torielli L; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy., Ferrandi M; Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy., Hamsten A; Cardiovascular Genetics and Genomics, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden., Soares-da-Silva P; BIAL - Portela & Ca, S.A., S. Mamede do Coronado, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal., Eriksson P; Cardiovascular Genetics and Genomics, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden., Bertorello AM; Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden., Brion L; Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2014 Apr 21; Vol. 9 (4), pp. e95771. Date of Electronic Publication: 2014 Apr 21 (Print Publication: 2014).
DOI: 10.1371/journal.pone.0095771
Abstrakt: Cardiac left ventricle hypertrophy (LVH) constitutes a major risk factor for heart failure. Although LVH is most commonly caused by chronic elevation in arterial blood pressure, reduction of blood pressure to normal levels does not always result in regression of LVH, suggesting that additional factors contribute to the development of this pathology. We tested whether genetic preconditions associated with the imbalance in sodium homeostasis could trigger the development of LVH without concomitant increases in blood pressure. The results showed that the presence of a hypertensive variant of α-adducin gene in Milan rats (before they become hypertensive) resulted in elevated expression of genes associated with LVH, and of salt-inducible kinase 2 (SIK2) in the left ventricle (LV). Moreover, the mRNA expression levels of SIK2, α-adducin, and several markers of cardiac hypertrophy were positively correlated in tissue biopsies obtained from human hearts. In addition, we found in cardiac myocytes that α-adducin regulates the expression of SIK2, which in turn mediates the effects of adducin on hypertrophy markers gene activation. Furthermore, evidence that SIK2 is critical for the development of LVH in response to chronic high salt diet (HS) was obtained in mice with ablation of the sik2 gene. Increases in the expression of genes associated with LVH, as well as increases in LV wall thickness upon HS, occurred only in sik2+/+ but not in sik2-/- mice. Thus LVH triggered by HS or the presence of a genetic variant of α-adducin requires SIK2 and is independent of elevated blood pressure. Inhibitors of SIK2 may constitute part of a novel therapeutic regimen aimed at prevention/regression of LVH.
Databáze: MEDLINE
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