Ablation of Hsp90β Reduces Myocardial Infarction

Myocardial infarction (MI) caused nearly 110,000 deaths in the United States in 2021. MI results from a complete blockage (ischemia) in one or more coronary arteries. Unfortunately, clearing the blockage (reperfusion) triggers significant cell death and permanent heart tissue damage. Preventing cell death during ischemia/reperfusion (I/R) injury is crucial for reducing heart damage and improving patient outcomes. Molecular chaperones are promising targets in I/R injury due to their pro-survival functions, yet the role of Hsp90β, the most abundant and constitutively active chaperone, remains unclear. To explore this, we developed a cardiomyocyte-specific Hsp90β conditional knockout mouse model. Surprisingly, Hsp90β ablation reduced infarct size after I/R injury compared to control. Studies on isolated mitochondria revealed that mitochondria from Hsp90β-deficient hearts were less sensitive to calcium-induced swelling, suggesting reduced opening of the mitochondrial permeability transition pore (mPTP) which decreases necrosis during I/R injury. Further, our experiments with mitochondrial protease inhibitors indicated that Hsp90β ablation may regulate the degradation rates of mPTP components. Concurrently, we observed changes in BAX/Bcl-2 and BAX/Bcl-xL ratios in Hsp90β-deficient hearts, hinting at protection from apoptosis in later reperfusion stages. This study provides insights into Hsp90β’s role in necrosis and apoptosis during I/R injury. Future research will focus on uncovering the protective mechanisms linked to Hsp90β ablation. IDeA awards from NIGMS (2P20GM113125 and 3P20GM139763-03S2) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.