PMID- 30188871
OWN - NLM
STAT- MEDLINE
DCOM- 20190618
LR  - 20190618
IS  - 1533-4023 (Electronic)
IS  - 0160-2446 (Linking)
VI  - 72
IP  - 5
DP  - 2018 Nov
TI  - Metformin Regulates the Expression of SK2 and SK3 in the Atria of Rats With Type 
      2 Diabetes Mellitus Through the NOX4/p38MAPK Signaling Pathway.
PG  - 205-213
LID - 10.1097/FJC.0000000000000615 [doi]
AB  - We previously found that metformin regulates the ion current conducted by the 
      small conductance calcium-activated potassium channels (SK channels) in the atria 
      of rats with type 2 diabetes mellitus (T2DM) as well as the mRNA and protein 
      expression of the SK2 and SK3 subtypes of SK channels. In this study, we 
      hypothesized that the nicotinamide adenine dinucleotide phosphate oxidase 4 
      (NOX4)/p38 mitogen-activated protein kinase (p38MAPK) signaling pathway was 
      involved in the metformin-mediated regulation of SK2 and SK3 expression in the 
      atria of rats with T2DM. We randomly divided Wistar rats into the control group, 
      the untreated T2DM group, the metformin-treated group, the group receiving 
      subcutaneous injections of the nicotinamide adenine dinucleotide phosphate 
      oxidase (NOX) inhibitor diphenyleneiodonium (DPI), and the group receiving tail 
      vein injections of the p38MAPK agonist anisomycin. Real-time polymerase chain 
      reaction, Western blot, and immunohistochemistry were applied to examine the 
      expression levels of SK2, SK3, NOX4, and phospho-p38MAPK (p-p38MAPK) mRNAs and 
      proteins in the atrial tissue of relevant groups. We observed that the expression 
      levels of NOX4 mRNA and protein and p-p38MAPK protein were significantly elevated 
      in the atria of rats with T2DM compared with the control group. In addition, SK2 
      protein expression was reduced, whereas SK3 protein expression was increased. The 
      8-week treatment with metformin markedly reduced the expression levels of NOX4 
      mRNA and protein and p-p38MAPK protein, upregulated the SK2 expression, and 
      downregulated the SK3 expression. Tail vein injection with anisomycin 
      significantly increased the p-p38MAPK expression while further inhibiting the 
      expression of SK2 and enhancing the expression of SK3. Subcutaneous injection 
      with DPI considerably inhibited the expression of NOX4, further enhanced the 
      expression of SK2 and suppressed the expression of SK3. In addition, subcutaneous 
      injection with DPI significantly suppressed the phosphorylation of p38MAPK. In 
      conclusion, the NOX4/p38MAPK signaling pathway mediates the downregulation of SK2 
      and the upregulation of SK3 in the atria of rats with T2DM. Long-term metformin 
      treatment upregulates SK2 protein expression and downregulates SK3 protein 
      expression by inhibiting the NOX4/p38MAPK signaling pathway.
FAU - Liu, Changhe
AU  - Liu C
AD  - Department of Cardiology, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Hua, Na
AU  - Hua N
AD  - Department of Otolaryngology, Affiliated Zhongshan Hospital of Dalian University, 
      Dalian, China.
FAU - Fu, Xi
AU  - Fu X
AD  - Department of Cardiology, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Pan, Yilong
AU  - Pan Y
AD  - Department of Cardiology, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Li, Bin
AU  - Li B
AD  - Department of Cardiology, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Li, Xiaodong
AU  - Li X
AD  - Department of Cardiology, Shengjing Hospital of China Medical University, 
      Shenyang, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Kcnn2 protein, rat)
RN  - 0 (Kcnn3 protein, rat)
RN  - 0 (Small-Conductance Calcium-Activated Potassium Channels)
RN  - 5W494URQ81 (Streptozocin)
RN  - 9100L32L2N (Metformin)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (Nox4 protein, rat)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Experimental/chemically induced/*drug 
      therapy/enzymology/genetics
MH  - Diabetes Mellitus, Type 2/chemically induced/*drug therapy/enzymology/genetics
MH  - Diabetic Cardiomyopathies/chemically induced/enzymology/genetics/*prevention & 
      control
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Heart Atria/*drug effects/enzymology
MH  - Hypoglycemic Agents/*pharmacology
MH  - Male
MH  - Metformin/*pharmacology
MH  - NADPH Oxidase 4/genetics/*metabolism
MH  - Phosphorylation
MH  - Rats, Wistar
MH  - Signal Transduction/drug effects
MH  - Small-Conductance Calcium-Activated Potassium Channels/genetics/*metabolism
MH  - Streptozocin
MH  - p38 Mitogen-Activated Protein Kinases/genetics/*metabolism
EDAT- 2018/09/07 06:00
MHDA- 2019/06/19 06:00
CRDT- 2018/09/07 06:00
PHST- 2018/09/07 06:00 [pubmed]
PHST- 2019/06/19 06:00 [medline]
PHST- 2018/09/07 06:00 [entrez]
AID - 10.1097/FJC.0000000000000615 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 2018 Nov;72(5):205-213. doi: 
      10.1097/FJC.0000000000000615.