Author + information
- Min Xie,
- Yongli Kong,
- Wei Tan,
- Herman May,
- Pavan Battiprolu,
- Zully Pedrozo,
- Zhao Wang,
- Nan Jiang,
- John Warner,
- Thomas G. Gillette,
- Aslan Turer and
- Joseph Hill
Whereas reperfusion injury accounts for up to 50% of the injury of ischemia/reperfusion (I/R), no therapies are available targeting this. Histone deacetylases (HDAC) inhibitor reduces infarct size by 50% in mouse I/R models. Translating these results to human, however, requires large animal testing and underlying mechanisms remain undefined. Here, we hypothesize that SAHA, an HDAC inhibitor which is FDA–approved for cancer, will a) blunt I/R injury by b) targeting reperfusion injury and c) through autophagy.
Twenty–one rabbits were randomized into 3 groups: a) DMSO control, b) SAHA pretreatment (one day before and at surgery), and c) SAHA reperfusion–only (at reperfusion) and subjected to I/R (30 min, 24h). This latter arm mimics the clinical situation where patients undergo PCI for STEMI. Western blots, electron microscopy (EM) and fluorescence imaging were used to detect autophagy.
SAHA reduced infarct size normalized to area at risk and partially rescued systolic function when given before surgery or only at reperfusion. Measured rabbit SAHA plasma concentration is achievable in human. In the infarct border zone, SAHA increased autophagy as measured by LC3II levels, a finding verified by EM. In mice expressing RFP–GFP–LC3 and subjected to I/R, SAHA increased autophagic flux at the border zone measured as LC3 and lysosome puncta. In cultured neonatal rat ventricular cardiomyocytes (NRVM) subjected to simulated I/R, SAHA treatment increased basal autophagic flux and maintained it during both ischemia and reperfusion. In contrast, DMSO–treated NRVMs had decreases in autophagy during I/R. SAHA–induced autophagic flux was corroborated by increased LC3 and lyososome puncta in NRVMs infected with adenovirus GFP–LC3 and lysotracker treatment. In NRVM, treatment with SAHA reduced I/R–induced cell death by around 40%. Removal of an essential autophagy protein, ATG7 abolished SAHA's cardiomyocyte protective effect.
Translationally, FDA–approved HDAC inhibitor, SAHA, reduces infarct size in a large animal model. Mechanistically, the cardioprotective effects of SAHA during I/R likely occur through normalizing autophagic flux.
Special Session North, Room 120
Sunday, March 10, 2013, 9:00 a.m.–9:15 a.m.
Session Title: Young Investigator Awards Competition: ACCF/Herman K. Gold Young Investigators Award in Molecular and Cellular Cardiology
Abstract Category: Molecular and Cellular Cardiology
Presentation Number: 402–8
- 2013 American College of Cardiology Foundation