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Published on: July 10, 2019
gp-91 mediates histone deacetylase inhibition-induced cardioprotection
Ting C Zhao1, Ling X Zhang, Guangmao Cheng
1Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, RI 02908, USA. tzhao@rwmc.org
Insights
Histone deacetylase (HDAC) inhibition protects the heart from injury. This cardioprotection depends on gp-91, a subunit of NADPH-oxidase, and involves reactive oxygen species (ROS) production.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Histone deacetylase (HDAC) inhibition has shown promise in protecting the heart against ischemia and reperfusion (I/R) injury.
- The precise molecular mechanisms underlying HDAC inhibition-induced cardioprotection remain largely unknown.
- NADPH oxidase, particularly its gp-91 subunit, is implicated in cellular signaling and oxidative stress.
Purpose of the Study:
- To investigate the role of gp-91, a subunit of NADPH-oxidase, in mediating the cardioprotective effects of HDAC inhibition.
- To elucidate the signaling cascade involving HDAC inhibition, gp-91, and reactive oxygen species (ROS) in cardiac protection.
Main Methods:
- Utilized wild-type and gp-91 knockout mice treated with trichostatin A (TSA), a potent HDAC inhibitor.
- Assessed cardiac function and infarct size following 30 minutes of ischemia and 30 minutes of reperfusion.
- Employed Western blot, immunostaining, and siRNA-mediated gene silencing in H9c2 cardiomyoblasts and PLB-985 cells to evaluate gp-91 expression, ROS production, and caspase-3 activation under simulated ischemia (SI).
Main Results:
- HDAC inhibition with TSA significantly improved ventricular functional recovery and reduced infarct size in wild-type mice.
- These cardioprotective effects were abolished in gp-91 knockout mice.
- TSA treatment increased myocardial gp-91 expression and ROS production, which was abrogated by gp-91 deletion or knockdown.
- TSA attenuated simulated ischemia-induced cell necrosis and caspase-3 activation, effects that were dependent on gp-91 presence.
Conclusions:
- The study identifies a critical role for gp-91 subunit of NADPH-oxidase in mediating HDAC inhibition-induced cardioprotection.
- A signaling cascade involving HDAC inhibition, increased gp-91 expression, ROS generation, and subsequent inhibition of apoptosis is proposed.
- Targeting this gp-91 dependent pathway may offer novel therapeutic strategies for preventing cardiac I/R injury.
Abstract:
We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91(-)(/-) mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1 mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pre-treatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91(+/+) cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91(phox)-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91(+/+) cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect.
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