Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction.
Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-α and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKα (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium.
Department of Pharmacology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.
Hamid
H
Soraya
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
Alexander S
AS
Clanachan
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Maryam
M
Rameshrad
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Nasrin
N
Maleki-Dizaji
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mahmoud
M
Ghazi-Khansari
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: garjania@tbzmed.ac.ir.
Alireza
A
Garjani
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D006439:Hemodynamics / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007545:Isoproterenol / Q000009:adverse effects; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009203:Myocardial Infarction / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*
D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol
AMP-activated protein kinase; Inflammation; Isoproterenol (PubChem CID: 3779); Metformin; Metformin (PubChem CID: 4091); Myocardial infarction; Toll-like receptor