title: Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake.
abstract: 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.
authors.affiliation: Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Sergej
authors.initials: S
authors.lastname: Popov
authors.affiliation: Laboratory of Cell Signaling and Metabolism, National Institute for Biomedical Innovation, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Research Institute, Osaka, Japan.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Research Institute, Osaka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Otani
authors.affiliation: Cell Biology, National Cerebral and Cardiovascular Research Institute, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: BIAL - Portela & Ca, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Pires
authors.affiliation: MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Pinho
authors.affiliation: Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.affiliation: Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Torielli
authors.affiliation: Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Ferrandi
authors.affiliation: Cardiovascular Genetics and Genomics, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: BIAL - Portela & Ca, S.A., S. Mamede do Coronado, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
authors.affiliation: Cardiovascular Genetics and Genomics, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
authors.affiliation: Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Brion
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology / Q000517:prevention & control*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000517:prevention & control*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
chemical_list: D017673:Sodium Chloride, Dietary; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases
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