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Neonatal and adult cardiomyocytes differ in their susceptibility to the proapoptotic protein bnip3 (LB657)
Abstract   Peer reviewed

Neonatal and adult cardiomyocytes differ in their susceptibility to the proapoptotic protein bnip3 (LB657)

Youngil Lee, Hwa‐youn Lee and Asa Gustaffson
The FASEB journal, Vol.28(S1)
Experimental Biology (04/2014)
04/2014
DOI: https://doi.org/10.1096/fasebj.28.1_supplement.lb657

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Abstract

Bnip3 is a BH3‐only protein that is upregulated during hypoxic condition and is known to cause cell death in many different cell types. Studies have found that overexpression of Bnip3 in neonatal cardiac myocytes (NCM) induces cell death in the absence of a hypoxic insult. Here, we compared the sensitivity of NCM and adult cardiac myocytes (ACM) to Bnip3‐mediated cell death under a normoxic condition. Freshly isolated NCM and ACM were infected with an adenovirus encoding either β‐galactosidase (β‐gal) or Bnip3 for 24 hours. TMRM and Yo‐Pro1 were used to detect the changes in mitochondrial membrane potential and apoptotic cell death, respectively. Interestingly, we found that overexpression of Bnip3 failed to induce significant cell death in ACM, whereas significant cell death was observed in NCM. Ultrastuctural analysis of ACM overexpressing Bnip3 revealed normal mitochondrial architecture. Instead, Bnip3 overexpression appeared to selectively activate mitochondrial autophagy under normoxic conditions. Moreover, overexpression of Bnip3 significantly augmented oxidative stress‐mediated cell death in ACM, suggesting that Bnip3 required the presence of additional stress to activate cell death in ACM. Bnip3 is known to induce ROS production and to investigate the mechanism underlying the difference in susceptibility to Bnip3‐mediated cell death between ACM and NCM, we examined levels of the antioxidant, manganese superoxide dismutase (MnSOD) in these cells. We found that MnSOD expression was significantly higher in ACM compared to NCM. Also, susceptibility to Bnip3‐mediated cell death was restored in ACM in the presence of 2‐ME (100μM), a pharmacological MnSOD inhibitor. Taken together, these results suggest that ACM are resistant to Bnip3 due to its enhanced antioxidant capacity and that additional stress is required to switch from Bnip3’s pro‐autophagy to pro‐death function. Supported by NIH R01 HL087023 Grant Funding Source: NIH R01 HL087023

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