PMID- 37920479
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240430
IS  - 2666-3503 (Electronic)
IS  - 2666-3503 (Linking)
VI  - 4
DP  - 2023
TI  - Vascular smooth muscle cell mechanotransduction through serum and glucocorticoid 
      inducible kinase-1 promotes interleukin-6 production and macrophage accumulation 
      in murine hypertension.
PG  - 100124
LID - 10.1016/j.jvssci.2023.100124 [doi]
LID - 100124
AB  - OBJECTIVE: The objective of this investigation was to demonstrate that in vivo 
      induction of hypertension (HTN) and in vitro cyclic stretch of aortic vascular 
      smooth muscle cells (VSMCs) can cause serum and glucocorticoid-inducible kinase 
      (SGK-1)-dependent production of cytokines to promote macrophage accumulation that 
      may promote vascular pathology. METHODS: HTN was induced in C57Bl/6 mice with 
      angiotensin II infusion (1.46 mg/kg/day x 21 days) with or without systemic 
      infusion of EMD638683 (2.5 mg/kg/day x 21 days), a selective SGK-1 inhibitor. 
      Systolic blood pressure was recorded. Abdominal aortas were harvested to quantify 
      SGK-1 activity (pSGK-1/SGK-1) by immunoblot. Flow cytometry quantified the 
      abundance of CD11b(+)/F480(+) cells (macrophages). Plasma interleukin (IL)-6 and 
      monocyte chemoattractant protein-1 (MCP-1) was assessed by enzyme-linked 
      immunosorbent assay. Aortic VSMCs from wild-type mice were subjected to 12% 
      biaxial cyclic stretch (Stretch) for 3 or 12 hours with or without EMD638683 
      (10 muM) and with or without SGK-1 small interfering RNA with subsequent 
      quantitative polymerase chain reaction for IL-6 and MCP-1 expression. IL-6 and 
      MCP-1 in culture media were analyzed by enzyme-linked immunosorbent assay. Aortic 
      VSMCs from SGK-1(flox+/+) mice were transfected with Cre-Adenovirus to knockdown 
      SGK-1 (SGK-1KD VSMCs) and underwent parallel tension experimentation. 
      Computational modeling was used to simulate VSMC signaling. Statistical analysis 
      included analysis of variance with significance at a P value of <.05. RESULTS: 
      SGK-1 activity, abundance of CD11b(+)/F4-80(+) cells, and plasma IL-6 were 
      increased in the abdominal aorta of mice with HTN and significantly reduced by 
      treatment with EMD638683. This outcome mirrored the increased abundance of IL-6 
      in media from Stretch C57Bl/6 VSMCs and attenuation of the effect with EMD638683 
      or SGK-1 small interfering RNA. C57Bl/6 VSMCs also responded to Stretch with 
      increased MCP-1 expression and secretion into the culture media. Further 
      supporting the integral role of mechanical signaling through SGK-1, target gene 
      expression and cytokine secretion was unchanged in SGK-1KD VSMCs with Stretch, 
      and computer modeling confirmed SGK-1 as an intersecting node of signaling owing 
      to mechanical strain and angiotensin II. CONCLUSIONS: Mechanical activation of 
      SGK-1 in aortic VSMCs can promote inflammatory signaling and increased macrophage 
      abundance, therefore this kinase warrants further exploration as a 
      pharmacotherapeutic target to abrogate hypertensive vascular pathology.
FAU - Figueroa, Mario
AU  - Figueroa M
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
FAU - Hall, SarahRose
AU  - Hall S
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
FAU - Mattia, Victoria
AU  - Mattia V
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
FAU - Mendoza, Alex
AU  - Mendoza A
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
FAU - Brown, Adam
AU  - Brown A
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
FAU - Xiong, Ying
AU  - Xiong Y
AD  - Division of Cardiothoracic Surgery, Medical University of South Carolina, 
      Charleston, SC.
FAU - Mukherjee, Rupak
AU  - Mukherjee R
AD  - Division of Cardiothoracic Surgery, Medical University of South Carolina, 
      Charleston, SC.
FAU - Jones, Jeffrey A
AU  - Jones JA
AD  - Division of Cardiothoracic Surgery, Medical University of South Carolina, 
      Charleston, SC.
AD  - Ralph H. Johnson VA Medical Center, Charleston, SC.
FAU - Richardson, William
AU  - Richardson W
AD  - Department of Chemical Engineering, University of Arkansas, Fayetteville, AK.
FAU - Ruddy, Jean Marie
AU  - Ruddy JM
AD  - Division of Vascular Surgery, Medical University of South Carolina, Charleston, 
      SC.
AD  - Ralph H. Johnson VA Medical Center, Charleston, SC.
LA  - eng
GR  - I01 BX000904/BX/BLRD VA/United States
GR  - K08 HL143169/HL/NHLBI NIH HHS/United States
GR  - R01 HL144927/HL/NHLBI NIH HHS/United States
GR  - T32 AR050958/AR/NIAMS NIH HHS/United States
PT  - Journal Article
DEP - 20230811
PL  - United States
TA  - JVS Vasc Sci
JT  - JVS-vascular science
JID - 101767073
PMC - PMC10618507
OTO - NOTNLM
OT  - Hypertension
OT  - Interleukin-6
OT  - Serum and glucocorticoid-inducible kinase-1 (SGK-1)
COIS- J.M.R. is a surgical proctor for CVRx, outside the scope of the submitted work.
EDAT- 2023/11/03 06:43
MHDA- 2023/11/03 06:44
PMCR- 2023/08/11
CRDT- 2023/11/03 03:57
PHST- 2022/12/27 00:00 [received]
PHST- 2023/08/01 00:00 [accepted]
PHST- 2023/11/03 06:44 [medline]
PHST- 2023/11/03 06:43 [pubmed]
PHST- 2023/11/03 03:57 [entrez]
PHST- 2023/08/11 00:00 [pmc-release]
AID - S2666-3503(23)00028-7 [pii]
AID - 100124 [pii]
AID - 10.1016/j.jvssci.2023.100124 [doi]
PST - epublish
SO  - JVS Vasc Sci. 2023 Aug 11;4:100124. doi: 10.1016/j.jvssci.2023.100124. 
      eCollection 2023.