Life, death, the unfolded protein response and apoptosis.

The unfolded protein response (UPR) occurs in cells in response to accumulation of unfolded proteins in the endoplasmic reticulum (ER).Whenunfolded protein accumulates secondary to a mild stress, universal protein synthesis is inhibited, but then resumes upon recovery. In contrast, a more severe or persistent stress would lead to apoptosis. UPR has not been extensively studied in the heart, though it has been described recently in association with some disease states such as hypertrophy and ischemia. In the current issue,Nickson et al. report the role of p53upregulated modulator of apoptosis (PUMA) in the apoptotic response to UPR in neonatal rat cardiac myocytes [1]. Nickson et al. found that UPR induced by either tunicamycin, which blocks glycosylation, or by thapsigargin, which reduces ER calcium, upregulated expression of PUMA beginning at 8 h for mRNAwith marked increase in PUMA protein observed at 12 h, and returned to normal by 48 h in isolated rat neonatal cardiomyocytes [1]. Induction of the UPR resulted in apoptosis, whichwasmanifest by 24 h andmaximal by 48h,with 40 to 70% of cells being apoptotic. Using an adenoviral shRNA, the authors blocked PUMA induction and greatly inhibited apoptosis. In a second approach, isolated mouse neonatal cardiomyocytes were prepared from wild-type, PUMA +/−, and PUMA −/− mice. Thapsigargin treatment induced apoptosis in the wild-type and PUMA heterozygotes, while the PUMA knockout mice were resistant to apoptosis, as measured by caspase-3 cleavage. Thus, PUMA has an important role in UPR-associated apoptosis in cardiac myocytes.