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Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease.

Abstract Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3β was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.
PMID
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Authors

Mayor MeshTerms
Keywords

AKT

Chronic kidney disease

Infarct size

Reperfusion

Signal transduction

Journal Title basic research in cardiology
Publication Year Start




PMID- 28421341
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 1435-1803 (Electronic)
IS  - 0300-8428 (Linking)
VI  - 112
IP  - 3
DP  - 2017 May
TI  - Insufficient activation of Akt upon reperfusion because of its novel modification
      by reduced PP2A-B55alpha contributes to enlargement of infarct size by chronic
      kidney disease.
PG  - 31
LID - 10.1007/s00395-017-0621-6 [doi]
AB  - Chronic kidney disease (CKD) increases myocardial infarct size by an unknown
      mechanism. Here we examined the hypothesis that impairment of protective
      PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to
      CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6
      nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and
      sham-operated rats served as controls (Sham group). Infarct size as a percentage 
      of area at risk after ischemia/reperfusion was significantly larger in the SNx
      group than in the Sham group (56.3 +/- 4.6 vs. 41.4 +/- 2.0%). In SNx group,
      myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced
      phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3beta was significantly
      suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by
      Ku-0063794 significantly increased infarct size in the Sham group but not in the 
      SNx group. There was no difference between the two groups in activities of mTORC2
      and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit
      B55alpha, which specifically targets Akt-Thr308, was reduced by 24% in the SNx
      group. Knockdown of B55alpha by siRNA increased baseline p-Akt-Thr308 and blunted
      Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in
      H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293
      cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results
      indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55alpha
      inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired
      Akt activation by insufficient Ser473 phosphorylation upon reperfusion
      contributes to infarct size enlargement by CKD.
FAU - Tobisawa, Toshiyuki
AU  - Tobisawa T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Yano, Toshiyuki
AU  - Yano T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Tanno, Masaya
AU  - Tanno M
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Miki, Takayuki
AU  - Miki T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Kuno, Atsushi
AU  - Kuno A
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Kimura, Yukishige
AU  - Kimura Y
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Ishikawa, Satoko
AU  - Ishikawa S
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Kouzu, Hidemichi
AU  - Kouzu H
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Nishizawa, Keitaro
AU  - Nishizawa K
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Yoshida, Hideaki
AU  - Yoshida H
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
FAU - Miura, Tetsuji
AU  - Miura T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
      University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
      [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170418
PL  - Germany
TA  - Basic Res Cardiol
JT  - Basic research in cardiology
JID - 0360342
OTO - NOTNLM
OT  - AKT
OT  - Chronic kidney disease
OT  - Infarct size
OT  - Reperfusion
OT  - Signal transduction
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2017/02/14 [received]
PHST- 2017/04/12 [accepted]
AID - 10.1007/s00395-017-0621-6 [doi]
AID - 10.1007/s00395-017-0621-6 [pii]
PST - ppublish
SO  - Basic Res Cardiol. 2017 May;112(3):31. doi: 10.1007/s00395-017-0621-6. Epub 2017 
      Apr 18.

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