Abstract 17009: Metformin Treatment Decreases the ER Stress-mediated Mitochondrial Injury
Introduction: Endoplasmic reticulum (ER) stress contributes to cardiovascular disease including heart failure. The ER and mitochondria (MITO) are closely connected. ER stress sensitizes mitochondrial permeability transition pore (MPTP) opening and damages the respiratory chain through calcium over load within MITO. Activation of AMP-activated protein kinase (AMPK) can inhibit ER stress. Metformin (MET) is a well-known anti-diabetic drug that activates the AMPK.
Hypothesis: We hypothesize that MET can protect MITO by inhibiting the ER stress through activation of AMPK.
Methods: ER stress was induced in mice through injection of thapsigargin (THAP) (3 mg/kg, I.P.). Mice were kept alive for 48 h. Mice in the MET group first received MET (dissolved in drinking water, 300mg/kg/day) for one week. Then, THAP was injected into mice followed by 48 h of continued MET treatment. Mice were euthanized at 48 h and MITO were isolated. Oxidative phosphorylation (OXPHOS, nAO/min/mg), calcium retention capacity [CRC (nmol Ca2+/mg), index of MPTP opening), and H2O2 generation (nmol/min/mg) were measured.
Results: THAP increased CHOP expression as an index of ER stress (not shown). ER stress decreased the rate of OXPHOS using complex I but not complex II substrates compared to vehicle-treated control (Table). ER stress sensitized to MPTP opening compared to control. The rate of H2O2 production was increased in MITO from ER stress hearts using succinate (Succ) + rotenone (ROT) as complex II substrate. MET improved OXPHOS with complex I substrates, inhibited the opening of MPTP, and decreased H2O2 production from MITO despite the induction of ER stress.
Conclusion: Treatment with MET protects MITO against damage from ER stress. Chronic supplementation of MET may be an alternative approach to decrease cardiac injury or slow aging process through attenuation of the ER stress-induced MITO and cardiac injury.
Author Disclosures: Q. Chen: None. J. Thompson: None. Y. Hu: None. E. Lesnefsky: None.
- © 2016 by American Heart Association, Inc.