PMID- 30545309 OWN - NLM STAT- MEDLINE DCOM- 20190815 LR - 20200827 IS - 1471-2261 (Electronic) IS - 1471-2261 (Linking) VI - 18 IP - 1 DP - 2018 Dec 13 TI - Metformin regulates atrial SK2 and SK3 expression through inhibiting the PKC/ERK signaling pathway in type 2 diabetic rats. PG - 236 LID - 10.1186/s12872-018-0950-x [doi] LID - 236 AB - BACKGROUND: Our previous study showed that metformin regulates the mRNA and protein levels of type 2 small conductance calcium-activated potassium channel (SK2) and type 3 small conductance calcium-activated potassium channels (SK3) in atrial tissue as well as the ion current of atrial myocytes in rats with type 2 diabetes mellitus (T2DM), but the underlying signaling mechanism is unknown. This study aimed to investigate whether metformin regulates atrial SK2 and SK3 protein expression in T2DM rats though the protein kinase C (PKC)/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: A T2DM rat model was established using a high-fat and high-sugar diet combined with a low-dose intraperitoneal injection of streptozotocin (STZ). The rats were randomly divided into the following five groups: the control group, the untreated T2DM group, the metformin-treated only group, the phorbol 12-myristate 13-acetate (PMA; a PKC agonist administered by intraperitoneal injection) treatment group, and the recombinant human epidermal growth factor (rh-EGF; an ERK agonist administered by tail vein injection) treatment group. The activity of PKC in atrial tissues was assayed by a PKC kinase activity assay kit. The protein expression of SK2, SK3, and phosphorylated ERK (pERK) were determined by western blotting and immunohistochemistry. RESULTS: Compared with the Control group, atrial PKC activity and pERK and SK3 protein expression were increased, while SK2 protein expression was decreased in atrial tissues of T2DM rats. Eight weeks of metformin treatment inhibited the PKC activity and pERK and SK3 expression, and elevated SK2 expression compared with the T2DM group. Compared with the metformin-treated only group, the injection of rh-EGF increased pERK and SK3 expression, and decreased SK2 expression; the injection of PMA increased PKC activity and SK3 expression, and decreased SK2 expression. In addition, the injection with PMA significantly elevated the expression of pERK. CONCLUSIONS: The PKC/ERK signaling pathway is involved in the downregulation of SK2 expression and the upregulation of SK3 expression in the atrium of T2DM rats. Long-term metformin treatment prevents the SK2 downregulation and the SK3 upregulation through inhibiting the PKC/ERK signaling pathway. FAU - Liu, Chang-He AU - Liu CH AD - Department of Cardiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China. FAU - Hua, Na AU - Hua N AD - Department of Otolaryngology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China. FAU - Fu, Xi AU - Fu X AD - Department of Cardiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China. FAU - Pan, Yi-Long AU - Pan YL AD - Department of Cardiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China. FAU - Li, Bin AU - Li B AD - Department of Cardiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China. FAU - Li, Xiao-Dong AU - Li XD AUID- ORCID: 0000-0002-8901-9896 AD - Department of Cardiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China. libin453930300@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181213 PL - England TA - BMC Cardiovasc Disord JT - BMC cardiovascular disorders JID - 100968539 RN - 0 (Hypoglycemic Agents) RN - 0 (Kcnn2 protein, rat) RN - 0 (Kcnn3 protein, rat) RN - 0 (Small-Conductance Calcium-Activated Potassium Channels) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) MH - Animals MH - Atrial Fibrillation/enzymology/prevention & control MH - Diabetes Mellitus, Experimental/blood/*drug therapy/enzymology MH - Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology MH - Extracellular Signal-Regulated MAP Kinases/*metabolism MH - Heart Atria/*drug effects/enzymology MH - Hypoglycemic Agents/*pharmacology MH - Male MH - Metformin/*pharmacology MH - Phosphorylation MH - Protein Kinase C/*metabolism MH - Rats, Wistar MH - Signal Transduction/drug effects MH - Small-Conductance Calcium-Activated Potassium Channels/*metabolism PMC - PMC6293565 OTO - NOTNLM OT - Atrial fibrillation OT - Diabetes mellitus OT - ERK OT - Metformin OT - PKC OT - SK channels COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The experiment protocol was approved by the Ethics Committee of Shengjing Hospital and conformed to the Guide for the Care and Use of Laboratory Animals by the US National Institutes of Health (NIH Publication No. 85-23). CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/12/14 06:00 MHDA- 2019/08/16 06:00 PMCR- 2018/12/13 CRDT- 2018/12/15 06:00 PHST- 2018/06/01 00:00 [received] PHST- 2018/11/09 00:00 [accepted] PHST- 2018/12/15 06:00 [entrez] PHST- 2018/12/14 06:00 [pubmed] PHST- 2019/08/16 06:00 [medline] PHST- 2018/12/13 00:00 [pmc-release] AID - 10.1186/s12872-018-0950-x [pii] AID - 950 [pii] AID - 10.1186/s12872-018-0950-x [doi] PST - epublish SO - BMC Cardiovasc Disord. 2018 Dec 13;18(1):236. doi: 10.1186/s12872-018-0950-x.