256 Chapter 9 diseases27–31 and prevented damage in the heart caused by ischemia/reperfusion.32–34 These findings suggest that enhancing the expression or activity of individual proteostasis network components could be therapeutically beneficial in PLN R14del DCM. Here, we showed that the small molecule BiX improved contractile performance without affecting Ca2+ transients in PLN R14del hiPSC-CMs. BiX preferentially activates ER stress response elements upstream of the BiP gene, a molecular chaperone, thereby increasing the activity of the UPR pathway.22 BiX showed a detrimental effect at high doses in hiPSC-CMs, suggesting a narrow therapeutic window between the effective doses and those at which it causes adverse toxic effects. The underlying mechanism for the biphasic response is unclear. It is possible that BiX is a ubiquitous ER stressor, limiting its application as a therapeutic strategy because it may activate several pathways of the UPR, including the ER stress–induced apoptotic pathways. Although the inotropic mechanisms of BiX are unprecedented, our findings suggest that selective modulation of UPR components could improve cardiac function in PLN R14del DCM and potentially avoid the deleterious effects that can occur with drugs that target calcium signaling or other upstream regulators of contraction. In conclusion, by combining scRNAseq, human cardiac tissue samples, and disease modeling in vitro using isogenic hiPSC-CMs, our findings implicate the UPR pathway in PLN R14del DCM pathogenesis. Furthermore, stimulating the UPR with the small molecule BiX led to functional rescue of the contractility deficit in PLN R14del hiPSC-CMs in vitro in a genotype-specific manner, suggesting UPR as a potential new therapeutic target. Finally, because disease penetrance in PLN R14del DCM is age related,35 we theorize that the decline in the proteostasis network capacity associated with aging36 may enhance the propensity of R14del PLN proteins to form aggregates, increasing disease susceptibility. Our study provides important proof of concept that activation of proteostasis mechanisms has a protective effect on PLN R14del-associated DCM in vitro and could be harnessed therapeutically to delay the onset or slow the progression of disease. ACKNOWLEDGEMENTS The authors are thankful to the patients and their families for providing valuable material for research purposes. They thank the Stanford CVI iPSC Biobank for providing the patient hiPSC lines and Dr Masayuki Miura for providing the XBP1-reporter vector. They gratefully acknowledge the help of Christian Snijders Blok and Dr Jan Willem Buikema.
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