Abstract 12722: Mitophagy Activation by Carbon Monoxide Improves Metabolic Syndrome-Induced Myocardial Dysfunction
Background: Carbon monoxide-releasing molecules (CO-RMs) may improve myocardial and mitochondrial functions. Here we tested whether treatment of mice with CORM-3 (Ru(CO)3Cl-glycinato) improves metabolic syndrome-induced cardiac and mitochondrial dysfunctions through changes in mitochondrial biogenesis, dynamics and mitophagy.
Methods and results: Mice (n=5-10) were fed for 12 weeks with either normal diet (ND) or high fat diet (HFD, 60% fat calories). Maximal aerobic capacity explored in exercising mice indicated lower oxygen uptake in HFD mice (117±1 vs. 124±2mLO2/kg/min, p<0.05 vs. ND). Myocardial function evaluated in a Langendorff preparation showed reduced force in HFD mice (431±84 vs. 694±40mg, p<0.05 vs. ND). Mitochondria from HFD hearts had reduced membrane potential (-209±1 vs. -217±3mV, p<0.05 vs. ND) and ADP-coupled respiration (64±4 vs 87±7pmolO2/s/mg, p<0.05 vs. ND). Electron microscopy showed significant increases in size (1.1±0.03 vs. 0.9±0.03µm²) and number (+22±7%) in the HFD hearts compared to ND. Consistently, HFD stimulated biogenesis as PGC-1a and NRF-1 mRNAs increased by 38 and 51%, respectively. Mitochondrial fusion signalling was also activated by HFD as Mfn2 and Opa1 expression raised by 37 and 58%, respectively. CORM-3 injection in HFD mice (10mg/kg, intraperitoneally, 36hrs before evaluation) improved maximal oxygen consumption (126±2mLO2/kg/min, p<0.05 vs. HFD) and heart function (675±28mg, p<0.05 vs. HFD). Membrane potential (-219±2mV) and respiration (74±3pmolO2/s/mg) were restored by CORM-3. As early as 36hrs after CORM-3 treatment, markers of biogenesis and fusion as well as mitochondrial morphology were back to normal. To understand such a quick effect, autophagy process was explored. While no differences were observed between ND and HFD, LC3II/LC3I ratio and Atg5 mRNA increased by 70% and 37% respectively in the HFD-CORM-3 group compared to ND.
Conclusions: Activation of autophagy by CORM-3 increases mitochondrial efficiency and in turn may improve HFD-induced cardiac dysfunction.
- © 2011 by American Heart Association, Inc.