Abstract 17243: A Role for Akt in the Crosstalk Between Cardiac Hypertrophy and Mitochondrial Biogenesis in Heart Failure
Background: Heart failure (HF) is characterized by mitochondrial remodeling and dysfunction but the underlying mechanisms of these defects are elusive. We assessed the hypothesis that decreased mitochondrial biogenesis may play a role and that this impairment is linked to cardiac hypertrophy.
Methods and results: Rats underwent aortic banding (AoB) to induce pathological hypertrophy. At 2 and 10 weeks after AoB, cardiac hypertrophy was present as shown by increased heart-to-body weight ratio. Consistently, phosphorylation of Akt, a key component of hypertrophic signaling, was markedly increased at these time points (4 and 2 fold; p<0.05). In contrast, mRNA expression of PGC-1α and its downstream target Tfam tended to decrease at 2 weeks and were significantly attenuated (both -52%; p<0.05) at 10 weeks, which indicates a progressive reduction of mitochondrial biogenesis signaling. In isolated neonatal rat cardiomyocytes, 1 μM angiotensin II (Ang II) increased Akt phosphorylation and caused hypertrophy, but affected neither protein expression of PGC-1α and Tfam nor mitochondrial content as assessed using MitoTracker®. However, Ang II at 10 μM sufficiently decreased mitochondrial content (-32%; p<0.01) in addition to hypertrophy induction, which may suggest impaired mitochondrial biogenesis. Importantly, co-incubation with Akt inhibitor VIII abolished Ang II-induced Akt phosphorylation and significantly blunted the effects of Ang II (10 μM) on cell size and mitochondrial content.
Conclusions: Impaired mitochondrial biogenesis may accompany cardiac hypertrophy and contribute to mitochondrial dysfunction in HF. Furthermore, the activation of Akt signaling may be involved in this defect of mitochondrial biogenesis. Therefore, in the development of HF, a crosstalk seems to exist between cardiac hypertrophy and mitochondrial biogenesis, in which Akt may acquire a central role.
- © 2013 by American Heart Association, Inc.