The second window of ischemic preconditioning (SWOP) provides maximal protection against ischemia through regulation of the inducible nitric oxide (NO) synthase (iNOS), yet its application is limited by the inconvenience of the preliminary ischemic stimulus required for prophylaxis. Over-expression of H11 kinase/Hsp22 (Hsp22) in a transgenic mouse model provides cardioprotection against ischemia that is equivalent to that conferred by SWOP. We hypothesized that short-term, prophylactic over-expression of Hsp22 would offer an alternative to SWOP in reducing ischemic damage through a NO-dependent mechanism. Adeno-mediated over-expression of Hsp22 was achieved in the area-at-risk of the left circumflex (Cx) coronary artery in chronically instrumented swine, and compared to LacZ controls (n=5 per group). Hsp22-injected myocardium showed an average 4-fold increase in Hsp22 protein expression compared to controls, and a doubling in iNOS expression (both, P<0.05). Four days after ischemia/reperfusion, regional wall thickening was reduced by 58±2% in Hsp22 group versus 82±7% in LacZ, and Hsp22 reduced infarct size by 40% (both, P<0.05 vs LacZ). Treatment with the NOS inhibitor L-NNA before ischemia suppressed the protection induced by Hsp22. In isolated cardiomyocytes, Hsp22 increased iNOS expression through the transcription factors NF-κB and STAT, the same effectors activated by SWOP, and reduced by 60% H2O2-mediated apoptosis, which was also abolished by NOS inhibitors. Therefore, short-term, prophylactic conditioning by Hsp22 provides NO-dependent cardioprotection that reproduces the signaling of SWOP, placing Hsp22 as a potential alternative for pre-emptive treatment of myocardial ischemia.
- heat shock protein
- gene delivery
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology