Metformin protects against infection-induced myocardial dysfunction

Abstract

Background and purpose: Metformin administration is associated with myocardial protection during ischemia and/or reperfusion, possibly via inhibition of inflammatory responses in the heart. Exposure to pathogens, in addition to the activation of the immune system and the associated metabolic dysfunction, often results in compromised myocardial function. We examined whether metformin administration could maintain the normal myocardial function in experimental moderate Gram negative infection, induced by lipopolysaccharide (LPS) administration.

Experimental approach: 129xC57BL/6 mice were divided into control groups that received either vehicle or a single intraperitoneal (i.p.) injection of low dose LPS (5mg/kg body wt), and metformin treated groups that received either daily metformin (4mg/kg/animal) i.p. injections for five days prior to LPS administration [Experiment 1], or a single metformin injection following same dose of LPS [Experiment 2].

Key results: LPS alone caused cardiac dysfunction, as confirmed by echocardiography, whereas metformin administration, either before or after LPS, rescued myocardial function. LPS caused marked reduction of the cardiac metabolism-related genes tested, including Prkaa2, Cpt1b, Ppargc1a and Ppargc1b; reduction of fatty acid oxidation, as reflected by the regulation of Ppara, Acaca and Acacb; increased glucose transport, as shown by Slc2a4 levels; reduction of ATP synthesis; significant increase of inflammatory markers, in particular IL6; and reduction of autophagy. Pretreatment with metformin normalized the levels of all these factors.

Conclusions and implications: We show for the first time that metformin protects the myocardium from LPS-associated myocardial dysfunction mainly by supporting its metabolic activity and allowing efficient energy utilization. Metformin can be a potential cardioprotective agent in individuals susceptible to exposure to pathogens.

Keywords: Bacterial infection; Cardiac dysfunction; Fatty acid oxidation; Lipopolysaccharide; Metformin.