Other
13 Authors
- Malhotra D,
- Wang Y,
- Lingrel JB,
- Li X,
- Liu L,
- Xie ZJ,
- Bai Y,
- Chen Y,
- Liu C,
- Sottejeau Y,
- Cooper CJ,
- Shapiro JI,
- Tian J
| First Author | Liu C | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 20 | Pages | 16390-8 |
| PubMed ID | 22451662 | Mgi Jnum | J:185445 |
| Mgi Id | MGI:5428796 | Doi | 10.1074/jbc.M111.304451 |
| Citation | Liu C, et al. (2012) Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis. J Biol Chem 287(20):16390-8 |
| abstractText | Decreases in cardiac Na/K-ATPase have been documented in patients with heart failure. Reduction of Na/K-ATPase alpha1 also contributes to the deficiency in cardiac contractility in animal models. Our previous studies demonstrate that reduction of cellular Na/K-ATPase causes cell growth inhibition and cell death in renal proximal tubule cells. To test whether reduction of Na/K-ATPase in combination with increased cardiotonic steroids causes cardiac myocyte death and cardiac dysfunction, we examined heart function in Na/K-ATPase alpha1 heterozygote knock-out mice (alpha1(+/-)) in comparison to wild type (WT) littermates after infusion of marinobufagenin (MBG). Adult cardiac myocytes were also isolated from both WT and alpha1(+/-) mice for in vitro experiments. The results demonstrated that MBG infusion increased myocyte apoptosis and induced significant left ventricle dilation in alpha1(+/-) mice but not in their WT littermates. Mechanistically, it was found that in WT myocytes MBG activated the Src/Akt/mTOR signaling pathway, which further increased phosphorylation of ribosome S6 kinase (S6K) and BAD (Bcl-2-associated death promoter) and protected cells from apoptosis. In alpha1(+/-) myocytes, the basal level of phospho-BAD is higher compared with WT myocytes, but MBG failed to induce further activation of the mTOR pathway. Reduction of Na/K-ATPase also caused the activation of caspase 9 but not caspase 8 in these cells. Using cultures of neonatal cardiac myocytes, we demonstrated that inhibition of the mTOR pathway by rapamycin also enabled MBG to activate caspase 9 and induce myocyte apoptosis. |
