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Increased Arterial ...
Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)
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- Bertorello, Alejandro M. (author)
- Karolinska Institute, Sweden
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- Pires, Nuno (author)
- Bial Portela and Ca SA, Portugal
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- Igreja, Bruno (author)
- Bial Portela and Ca SA, Portugal
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- Joao Pinho, Maria (author)
- University of Porto, Portugal
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- Vorkapic, Emina (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Hälsouniversitetet,Karolinska Institute, Sweden
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- Wågsäter, Dick (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Hälsouniversitetet,Karolinska Institute, Sweden
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- Wikstrom, Johannes (author)
- AstraZeneca RandD, Sweden
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- Behrendt, Margareta (author)
- AstraZeneca RandD, Sweden
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- Hamsten, Anders (author)
- Karolinska Institutet,Karolinska Institute, Sweden
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- Eriksson, Per (author)
- Karolinska Institutet,Karolinska Institute, Sweden
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- Soares-da-Silva, Patricio (author)
- Bial Portela and Ca SA, Portugal; University of Porto, Portugal
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- Brion, Laura (author)
- Karolinska Institute, Sweden
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(creator_code:org_t)
- American Heart Association, 2015
- 2015
- English.
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In: Circulation Research. - : American Heart Association. - 0009-7330 .- 1524-4571. ; 116:4, s. 642-U190
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
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- 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-beta 1 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-beta 1 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-beta 1-signaling inhibition.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Keyword
- endothelin-1; muscle
- smooth
- vascular; SIK1 protein
- human; vascular remodeling
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Bertorello, Alej ...
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Pires, Nuno
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Igreja, Bruno
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Joao Pinho, Mari ...
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Vorkapic, Emina
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Wågsäter, Dick
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Wikstrom, Johann ...
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Behrendt, Margar ...
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Hamsten, Anders
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Eriksson, Per
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Soares-da-Silva, ...
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Brion, Laura
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
- Articles in the publication
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Circulation Rese ...
- By the university
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Linköping University
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Karolinska Institutet