SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: Pressure-related effects

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

BACKGROUND Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart. METHODS Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies. RESULTS An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure. CONCLUSIONS The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.

Original languageEnglish (US)
Pages (from-to)846-856
Number of pages11
JournalAmerican journal of hypertension
Volume27
Issue number6
DOIs
StatePublished - Jan 1 2014

Fingerprint

Cell Death
Inflammation
Pressure
Interleukin-27
Interleukin-17
Interleukin-10
Reperfusion
Ischemia
Transcription Factor CHOP
Cytokines
Mechanical Stress
Mitochondrial Membrane Potential
DNA Damage
Coronary Disease
Flow Cytometry
Anti-Inflammatory Agents
Necrosis
Western Blotting
serum-glucocorticoid regulated kinase
Apoptosis

Keywords

  • GADD153
  • SGK-1
  • blood pressure
  • cell death
  • heart
  • hypertension
  • inflammation
  • ischemia reperfusion
  • pressure overload

ASJC Scopus subject areas

  • Internal Medicine

Cite this

SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart : Pressure-related effects. / Baban, Babak; Liu, Jun Yao; Mozaffari, Mahmood S.

In: American journal of hypertension, Vol. 27, No. 6, 01.01.2014, p. 846-856.

Research output: Contribution to journalArticle

@article{73c3b130100e4ac691b5bb951a7ce9a7,
title = "SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: Pressure-related effects",
abstract = "BACKGROUND Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart. METHODS Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies. RESULTS An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure. CONCLUSIONS The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.",
keywords = "GADD153, SGK-1, blood pressure, cell death, heart, hypertension, inflammation, ischemia reperfusion, pressure overload",
author = "Babak Baban and Liu, {Jun Yao} and Mozaffari, {Mahmood S}",
year = "2014",
month = "1",
day = "1",
doi = "10.1093/ajh/hpt269",
language = "English (US)",
volume = "27",
pages = "846--856",
journal = "American Journal of Hypertension",
issn = "0895-7061",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart

T2 - Pressure-related effects

AU - Baban, Babak

AU - Liu, Jun Yao

AU - Mozaffari, Mahmood S

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUND Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart. METHODS Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies. RESULTS An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure. CONCLUSIONS The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.

AB - BACKGROUND Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart. METHODS Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies. RESULTS An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure. CONCLUSIONS The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart.

KW - GADD153

KW - SGK-1

KW - blood pressure

KW - cell death

KW - heart

KW - hypertension

KW - inflammation

KW - ischemia reperfusion

KW - pressure overload

UR - http://www.scopus.com/inward/record.url?scp=84900851826&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84900851826&partnerID=8YFLogxK

U2 - 10.1093/ajh/hpt269

DO - 10.1093/ajh/hpt269

M3 - Article

C2 - 24429675

AN - SCOPUS:84900851826

VL - 27

SP - 846

EP - 856

JO - American Journal of Hypertension

JF - American Journal of Hypertension

SN - 0895-7061

IS - 6

ER -