Korean J Physiol Pharmacol.  2010 Dec;14(6):377-384. 10.4196/kjpp.2010.14.6.377.

Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice

• Cha HN
• Choi JH
• Kim YW
• Kim JY
• Ahn MW
• Park SY

• KMID: 2071709
• DOI: http://doi.org/10.4196/kjpp.2010.14.6.377

Abstract

The present study examined whether metformin treatment prevents isoporterenol-induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-beta, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP-2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-beta, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress.

Keyword

Metformin; Cardiac hypertrophy; Oxidative stress; AMPK; Isoproterenol

MeSH Terms

AMP-Activated Protein Kinases
Animals
Atrial Natriuretic Factor
Cardiomegaly
Collagen
Glutathione Peroxidase
Heart
Infusions, Subcutaneous
Injections, Intraperitoneal
Interleukin-6
Isoproterenol
Metformin
Mice
Oxidative Stress
RNA, Messenger
Transforming Growth Factor beta
Transforming Growth Factors
Tyrosine
AMP-Activated Protein Kinases
Atrial Natriuretic Factor
Collagen
Glutathione Peroxidase
Interleukin-6
Isoproterenol
Metformin
RNA, Messenger
Transforming Growth Factor beta
Transforming Growth Factors
Tyrosine

Figure

• 

  Fig. 1. Heart weight (A) and left ventricular posterior wall thickness (LVPW) measured using echocardiography (B) in mice. Mice were infused with saline (control), isoproterenol (ISO), metformin (MET) or metformin with isoproterenol (MET + ISO) for I week using osmotic minipumps. Data is expressed as mean±SE. Experimental cases are 6∼9. ∗p<0.05 vs. Control and #p<0.05 vs. ISO.

• 

  Fig. 2. Gene expression of transforming growth factor-β (TFG-β) (A), interleukin-6 (IL-6) (B), and atrial natriuretic peptide (ANP) (C) in the heart of saline (control), isoproterenol (ISO), metformin (MET) or metformin with isoproterenol (MET + ISO) infused mice for 1 week using osmotic minipumps. Data is expressed as mean± SE. Experimental cases are 6∼9. ∗p<0.05 vs. Control and #p<0.05 vs. ISO.

• 

  Fig. 3. Gene expression of collagen-1 (A), collage-3 (B), matrix metallopeptidase 2 (MMP-2) (C), and MMP-9 (D) in the heart of saline (control), isoproterenol (ISO), metformin (MET) or metformin with isoproterenol (MET + ISO) infused mice for 1 week using osmotic minipumps. Data is expressed as mean±SE. Experimental cases are 6∼9. ∗p<0.05 vs. Control.

• 

  Fig. 4. AMPK activity measured as phosphorylation of AMPK (pAMPK) in heart (A) and skeletal muscle (B) of saline (control), isoproterenol (ISO), metformin (MET) or metformin with isoproterenol (MET + ISO) infused mice for 1 week using osmotic minipumps. Experimental cases are 6∼9. ∗p<0.05 vs. Control.

• 

  Fig. 5. AMPK activity measured as phosphorylation of AMPK (pAMPK) in heart. Metformin (150 mg/kg/24 h) was subcutaneously infused using osmotic minipump for 2, 4, 24, and 48 h (A). Metformin (10 mg/kg) was intraperitoneally injected into mice and pAMPK and AMPK level were measured 1 h after injection (B). Control mice were treated with saline. Experimental cases are 5∼7. ∗p<0.05 vs. Saline.

• 

  Fig. 6. Nitrotyrosine level (A) and gene expression of glutathione peroxidase 1 (GPx1) (B) in heart of saline (control), isoproterenol (ISO), metformin (MET) or metformin with isoproterenol (MET + ISO) infused mice for 1 week using osmotic minipumps. Data is expressed as mean±SE. Experimental cases are 6∼9. ∗p<0.05 vs. Control and #p<0.05 vs. ISO.

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