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Published on: September 25, 2017
Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3
Vinodkumar B Pillai1, Sadhana Samant1, Nagalingam R Sundaresan1
1Departments of Surgery, University of Chicago, Chicago, Illinois, USA.
Insights
Honokiol (HKL), a natural compound, effectively blocks and reverses cardiac hypertrophy in mice by activating the deacetylase Sirt3. This compound enhances mitochondrial function and reduces harmful reactive oxygen species (ROS).
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Honokiol (HKL) is a natural biphenolic compound from magnolia trees with known anti-inflammatory, anti-oxidative, anti-tumour, and neuroprotective properties.
- Cardiac hypertrophy is a significant risk factor for heart failure, and effective pharmacological interventions are needed.
Purpose of the Study:
- To investigate the potential of Honokiol (HKL) in blocking and reversing cardiac hypertrophy.
- To elucidate the underlying molecular mechanisms, particularly the role of the deacetylase Sirt3.
Main Methods:
- Mice models were used to study agonist-induced and pressure overload-mediated cardiac hypertrophy.
- Mitochondrial function, reactive oxygen species (ROS) synthesis, and Sirt3 activity were assessed.
- Cardiac fibroblast proliferation and differentiation were analyzed in vitro.
Main Results:
- HKL effectively blocked and ameliorated pre-existing cardiac hypertrophy in mice.
- HKL treatment significantly enhanced Sirt3 expression and activity, leading to reduced acetylation of Sirt3 substrates like MnSOD and OSCP.
- HKL increased mitochondrial oxygen consumption and reduced ROS synthesis in wild-type cells, but not in Sirt3-knockout cells.
- HKL inhibited cardiac fibroblast proliferation and differentiation in a Sirt3-dependent manner.
Conclusions:
- Honokiol (HKL) acts as a pharmacological activator of Sirt3.
- HKL demonstrates significant potential in treating cardiac hypertrophy by modulating mitochondrial function and fibroblast activity.
- These findings suggest HKL as a promising therapeutic agent for cardiac hypertrophy.
Abstract:
Honokiol (HKL) is a natural biphenolic compound derived from the bark of magnolia trees with anti-inflammatory, anti-oxidative, anti-tumour and neuroprotective properties. Here we show that HKL blocks agonist-induced and pressure overload-mediated, cardiac hypertrophic responses, and ameliorates pre-existing cardiac hypertrophy, in mice. Our data suggest that the anti-hypertrophic effects of HKL depend on activation of the deacetylase Sirt3. We demonstrate that HKL is present in mitochondria, enhances Sirt3 expression nearly twofold and suggest that HKL may bind to Sirt3 to further increase its activity. Increased Sirt3 activity is associated with reduced acetylation of mitochondrial Sirt3 substrates, MnSOD and oligomycin-sensitivity conferring protein (OSCP). HKL-treatment increases mitochondrial rate of oxygen consumption and reduces ROS synthesis in wild type, but not in Sirt3-KO cells. Moreover, HKL-treatment blocks cardiac fibroblast proliferation and differentiation to myofibroblasts in a Sirt3-dependent manner. These results suggest that HKL is a pharmacological activator of Sirt3 capable of blocking, and even reversing, the cardiac hypertrophic response.
