Abstract 3342: Mitochondrial Dynamics as a Target for Cardioprotection During Post-infarction Remodelling in Rats
Background: Studies on the role of mitochondrial fission/fusion (MFF) proteins in the heart has been initiated recently due to their biological significance in cell metabolism. In this study, we hypothesized that MFF machinery is affected by post-infarction remodelling and serves as a target for the Na+/H+ exchanger 1 (NHE-1) specific inhibitor EMD-87580 (EMD).
Methods: First, adult calcium-tolerant ventricular cardiomyocytes were isolated from Sprague-Dawley rats and used for confocal microscopy and Western blotting to ensure the presence of MFF proteins. Second, male Sprague-Dawley rats were subjected to coronary artery ligation (CAL) or a sham procedure and followed for 12 or 18 weeks in the following 4 groups: sham (n=9), sham+EMD (n=8), CAL (n=8) and CAL+EMD (n=9). Mitochondrial fission (Fis1 and Drp1) and fusion (Mfn2 and OPA1) proteins were analysed in heart homogenates by Western blotting.
Adult cardiomyocytes express all four proteins required for MFF.
CAL increased Fis1 by 73% (P<0.01) and 31% (P<0.05) at 12 and 18 weeks, respectively, whereas Drp1 expression was not affected by CAL.
Mfn2 was reduced by 22% (P<0.05) and 17% (P<0.05) in hearts following 12 and 18 weeks CAL, respectively. OPA1 was not changed at 12 weeks, although its expression decreased by 17% (P<0.05) 18 weeks after CAL. Alterations in the expression of the MFF proteins were associated with mitochondrial dysfunction as evidenced by a decreased State 3 respiration and increased permeability transition pore opening. EMD significantly inhibited Fis1 and increased Mfn2 expression thus normalizing the ratio of fission-to-fusion proteins that was associated with reduced cardiac hypertrophy. The effect of EMD may be mediated at least in part through its direct action on mitochondria since in a separate set of experiments we demonstrated that Percoll-purified mitochondria contain NHE-1.
Conclusion: Our study provides the first evidence linking post-infarction remodelling with alterations in MFF proteins expression that was abrogated by NHE-1 inhibition. Mitochondrial dynamics may be a target for reduction of mitochondrial dysfunction induced by various cardiac stressors such as post-infarction remodelling and heart failure.