Abstract 16685: Honokiol Blocks Cardiac Hypertrophic Response via Activation of SIRT3
Background: Honokiol (HKL) is a polyphenolic molecule originally isolated from the Magnolia plants. HKL has anti-oxidative, anti-proliferative, anti-inflammatory and anti-cancer properties. Since polyphenolic compounds are known to induce NAD/NADH ratio and favor activation of sirtuins, we investigated whether HKL can activate cardiac SIRT3 levels and hence attenuate the cardiac hypertrophic response.
Methods and Results: Treatment of primary cultures of neonatal rat cardiomyocytes with HKL dose dependently increased NAD/NADH ratio and SIRT3 mRNA and protein levels. SIRT3 activation was also confirmed by reduced acetylation of MnSOD at K68 residue, a specific site of SIRT3-dependent deacetylation. To examine the impact of HKL on cardiac hypertrophy, cardiomyocytes were treated with 20 µM phenylephrine (PE) for 24 hours, with or without HKL. We found that exogenous addition of 5 μ M HKL blocked the PE-induced [3H] leucine incorporation into cellularproteins, sarcomere organization, ANF release from nuclei and NFAT induction, thus suggesting that HKL has the ability to block the hypertrophic response of cardiomyocytes. HKL treatment also reduced cardiac fibroblast (CF) proliferation and showed reduced expression of myofibroblast differentiation markers, such as collagen and smooth muscle α-actin expression. This anti-fibrotic effect of HKL was, however, not observed in SIRT3 deficient CFs, thus suggesting that HKL blocks CF differentiation to myofibroblasts via activation of SIRT3. To examine the anti-hypertrophic effect of HKL in vivo, we induced cardiac hypertrophy in mice by transverse aortic constriction (TAC) and treated animals daily with a dose of 2mg/kg of HKL. We found that HKL treatment resulted in 80% reduced HW/BW ratio, 5 fold reduced fetal gene expression (ANF, and βMHC) and cardiac fibrosis, compared to HKL untreated animals. Furthermore, TAC mice showed reduced SIRT3 and elevated MnSOD acetylation levels, whereas banded mice treated with HKL maintained SIRT3 levels and deacetylation of MnSOD, similar to sham operated controls.
Conclusion: From these studies we have discovered a pharmacological activator of SIRT3, which is capable of blocking cardiac hypertrophic response both in vitro and in vivo models of hypertrophy.
- © 2012 by American Heart Association, Inc.