Novel Role of HAX-1 in Ischemic Injury Protection: Involvement of Hsp90
Rationale: Ischemic heart disease is characterized by contractile dysfunction and increased cardiomyocyte death, induced by necrosis and apoptosis. Increased cell survival after an ischemic insult is critical and depends on several cellular pathways, which have not been fully elucidated.
Objective: To test the hypothesis that the anti-apoptotic haematopoietic-lineage-substrate-1-associated protein-X-1 (HAX-1), recently identified as regulator of cardiac Ca-cycling, may also ameliorate cellular injury in the face of an ischemic insult.
Methods and Results: We report that cardiac ischemia/reperfusion injury is associated with significant decreases in HAX-1 levels ex vivo and in vivo. Accordingly, over-expression of HAX-1 improved contractile recovery, coupled with reduced infarct size, plasma troponin I level and apoptosis. The beneficial effects were associated with decreased ER stress response through specific inhibition of the inositol-requiring-enzyme (IRE-1) signaling pathway, including its downstream effectors caspase-12 and the transcription factor C/EBP homologous protein. Conversely, HAX-1 heterozygous deficient hearts exhibited increases in infarct size and IRE-1 activity. The inhibitory effects of HAX-1 were mediated by its binding to the N-terminal fragment of the heat shock protein 90 (Hsp90). Moreover, HAX-1 sequestered Hsp90 from IRE-1 to the phospholamban/SERCA calcium transport complex. The HAX-1 regulation was further supported by loss of IRE-1 inhibition in presence of the Hsp90 inhibitor, 17-N-Allylamino-17-Demethoxygeldanamycin.
Conclusions: Cardiac ischemia/reperfusion injury is associated with decreases in HAX-1 levels. Consequently, over-expression of HAX-1 promotes cardiomyocyte survival, mediated by its interaction with Hsp90 and specific inhibition of IRE-1 signaling at the ER/SR.
- Received August 16, 2012.
- Accepted September 14, 2012.
- Copyright © 2012, American Heart Association