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Increased arterial blood pressure and vascular remodeling in mice lacking salt-inducible kinase 1 (SIK1).

AbstractRATIONALE:
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.
AuthorsAlejandro M Bertorello, Nuno Pires, Bruno Igreja, Maria João Pinho, Emina Vorkapic, Dick Wågsäter, Johannes Wikström, Margareta Behrendt, Anders Hamsten, Per Eriksson, Patricio Soares-da-Silva, Laura Brion
JournalCirculation research (Circ Res) Vol. 116 Issue 4 Pg. 642-52 (Feb 13 2015) ISSN: 1524-4571 [Electronic] United States
PMID25556206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 American Heart Association, Inc.
Chemical References
  • Endothelin-1
  • Sodium Chloride, Dietary
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Collagen
  • Protein Serine-Threonine Kinases
  • SIK1 protein, human
  • Sik1 protein, mouse
Topics
  • Adventitia (enzymology, pathology)
  • Animals
  • Aorta (enzymology, pathology, physiopathology)
  • Arterial Pressure
  • Cells, Cultured
  • Collagen (metabolism)
  • Endothelin-1 (metabolism)
  • Fibroblasts (enzymology, pathology)
  • Genotype
  • Humans
  • Hypertension (enzymology, etiology, genetics, pathology, physiopathology)
  • Mice, Knockout
  • Muscle, Smooth, Vascular (enzymology, pathology, physiopathology)
  • Myocytes, Smooth Muscle (enzymology, pathology)
  • Natriuresis
  • Phenotype
  • Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
  • RNA Interference
  • Signal Transduction
  • Sodium Chloride, Dietary
  • Sympathetic Nervous System (physiopathology)
  • Transfection
  • Transforming Growth Factor beta1 (metabolism)
  • Vascular Remodeling
  • Vasoconstriction

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