Author + information
- Nicolas Noiseux,
- Samer Mansour,
- Henry Aceros,
- Louis-Mathieu Stevens and
- Shant DerSarkissian
Background: We were first to report that Celastrol, an HSP90 inhibitor possessing antioxidant properties, reduces ischemic injury and preserves cardiac function in a rat model of permanent coronary ligation. Celastrol activates pro-survival kinases, the heat shock and antioxidant responses (HSR and AR) leading to overexpression of cytoprotective proteins including heme-oxygenase 1 (HO-1, HSP32). Our objective is to investigate the protective potential of Celastrol in the clinically relevant ischemia/ reperfusion (I/R) injury.
Methods: Combining in vitro cell culture, ex vivo Langendorff isolated rat heart perfusion with 30 min global ischemia followed by 120 min reperfusion (I/R injury), and in vivo I/R rat MI, we evaluated the infarct sparing effects of Celastrol.
Results: In H9c2 rat cardiomyoblast cell cultures, Celastrol (10-6M, best dose) increased cellular viability (Live/dead kit) to hypoxic stress (<1%O2, 48h) by 12.8±1.0%, to oxidative stress (H2O2 0.75mM, 1h) by 14.5±1.5% and to I/R stress (<1% O2, 18h; 6h normoxia) by 15.2±5.2% (N=5-7, all p<0.05). In Langendorff, Celastrol (10-7M, best dose) reduced infarct size by 1.7 fold (p=0.047), reduced troponin T release by 3.1 fold at 60min (p=0.005), preserved LV contractility (+dP/dt, contractility index, and generated pressure) and relaxation (EDP, -dP/dt) (all p<0.001). In Lewis rats with 30 min coronary occlusion followed by reopening, a single dose of Celastrol (1 mg/kg) at time of reperfusion preserved cardiac function. At 24hr, LVEF and cardiac output were reduced by 30% and 38% in vehicle treated animals, vs 6% and 21% respectively in Celastrol treated animals (P<0.05, N=6-8). Celastrol reduces serum levels of troponin T and lactate dehydrogenase (LDH), both tissue injury biomarkers. In infracted heart tissue, protein levels of HO-1 and HSP70 were upregulated in Celastrol treated animals.
Conclusions: Based on its protective effects, Celastrol and similar molecules are being investigated in our laboratory in a preclinical development plan geared towards the discovery of novel protective adjunct treatment to clinical reperfusion protocols.
Poster Hall, Hall C
Saturday, March 18, 2017, 9:45 a.m.-10:30 a.m.
Session Title: Novel Imaging and Therapies in Heart Failure
Abstract Category: 12. Heart Failure and Cardiomyopathies: Basic
Presentation Number: 1200-261
- 2017 American College of Cardiology Foundation