Abstract Body: Chaperone proteins have become exciting new targets in the treatment of cardiovascular diseases due to their pro-survival functions. The most abundant, constitutively expressed chaperone in the heart, heat shock protein 90 beta (Hsp90β), is believed to operate primarily in the cytosol to help fold and stabilize hundreds of proteins and facilitate intracellular signaling. Although Hsp90β influences so many different proteins and pathways, current literature about its role in the heart is limited due to the use of pan-inhibitors which target all isoforms of Hsp90. To elucidate the function of Hsp90β, we generated a cardiac-specific Hsp90β conditional knockout (cKO) mouse model.

Following Hsp90β cKO mice for 1 year after gene ablation, we surprisingly observed no compromise in animal survival and minimal changes in heart structure and function, which is against its suggested pro-survival role. Transmission electron microscopy (TEM) showed that Hsp90β cKO mitochondria were larger with more tightly packed cristae than the control after 1-year. The increase in mitochondrial compaction was also observed only 7 days after gene ablation, suggesting that it was not a result of long-term compensation. We then isolated the mitochondria from control and Hsp90β cKO hearts to perform the swelling and calcium retention assays. Both assays suggest that Hsp90β cKO mitochondria have enhanced capacity for calcium uptake before they rupture. Based on findings from western blots, the mechanism appears to be driven by a reduction in cyclophilin D expression. Lastly, after subjecting the hearts to ischemia/reperfusion injury, TEM data showed more preserved mitochondrial structure in Hsp90β cKO hearts, which is consistent to the observed reduction in infarct size. Together, these results suggest that cardiac Hsp90β does not operate as a pro-survival chaperone as suggested, and loss of Hsp90β can preserve mitochondrial membrane integrity upon stress.