252 Chapter 9 (23±5%), but we also detected comparable BiP expression in desmosomal arrhythmogenic right ventricular cardiomyopathy (16±5%) and ischemic cardiomyopathy (17±2%) relative to control hearts (2±1%; Figure 3E–3H and 3M), consistent with UPR activation in failing hearts.16–18 Protein disulfide isomerase, a protein folding facilitator, is another chaperone that is induced by protein misfolding.19 A striking protein disulfide isomerase presence was detected in the myocardium of patients with PLN R14del (46±29%) relative to subjects with desmosomal arrhythmogenic right ventricular cardiomyopathy (7±6%), those with ischemic cardiomyopathy (6±4%), and control subjects (3±3%; Figure 3I–3M). In addition, RNA sequencing showed that UPR genes are upregulated in the myocardium of R14del patient cardiac tissue relative to that of healthy individuals (Figure 3N). Taken together, the histological manifestations of PLN R14del share hallmarks of neurodegenerative disease wherein the accumulation of protein aggregates is associated with abnormal levels of ER stress response.20,21 Figure 3. Determination of the unfolded protein response (UPR) status in phospholamban (PLN) loss of arginine at position 14 (R14del) disease and other forms of cardiomyopathies. Histological analysis of human myocardium from patients with PLN R14del, desmosomal arrhythmogenic cardiomyopathy (ARVC), and ischemic cardiomyopathy (ICM) vs control (CON; healthy) hearts. A through D, Abnormal accumulation of PLN in perinuclear aggregates (arrows) in severely affected cardiomyocytes (CMs) in PLN R14del and absent in ARVC, ICM, and control. E through H, Diffuse moderate immunolabeling (arrows) for BiP (binding immunoglobulin protein) in PLN 14del and present to a lesser extent in ARVC and ICM. I through L, High immunolabeling for dotted cytoplasmic protein disulfide isomerase (PDI; arrows) in PLN 14del and low PDI presence in ARVC and ICM (scale bar=25 µm). M, Quantification of immunostaining in PLN R14del (n=6 patients), ARVC (n=3 patients), ICM (n=3 patients), and control (n=3 patients). N, RNA sequence analysis of UPR gene expression from healthy and PLN R14del myocardium from patient samples. Data are presented as mean±SEM. *P<0.00005.
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