Alejandro M Bertorello1, Nuno Pires1, Bruno Igreja1, Maria João Pinho1, Emina Vorkapic1, Dick Wågsäter1, Johannes Wikström1, Margareta Behrendt1, Anders Hamsten1, Per Eriksson1, Patricio Soares-da-Silva1, Laura Brion2. 1. From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.). 2. From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.). laura.brion@ki.se.
Abstract
RATIONALE: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. OBJECTIVE: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. METHODS AND RESULTS: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1(+/+) mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. CONCLUSIONS: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-β1-signaling inhibition.
RATIONALE: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. OBJECTIVE: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. METHODS AND RESULTS:SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1(+/+) mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. CONCLUSIONS:Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-β1-signaling inhibition.
Authors: Johanna Säll; Annie M L Pettersson; Christel Björk; Emma Henriksson; Sebastian Wasserstrom; Wilhelm Linder; Yuedan Zhou; Ola Hansson; Daniel P Andersson; Mikael Ekelund; Eva Degerman; Karin G Stenkula; Jurga Laurencikiene; Olga Göransson Journal: Diabetologia Date: 2016-11-02 Impact factor: 10.122
Authors: Mark Nixon; Randi Stewart-Fitzgibbon; Jingqi Fu; Dmitry Akhmedov; Kavitha Rajendran; Maria G Mendoza-Rodriguez; Yisel A Rivera-Molina; Micah Gibson; Eric D Berglund; Nicholas J Justice; Rebecca Berdeaux Journal: Mol Metab Date: 2015-11-06 Impact factor: 7.422