Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt
Takahiro Kato, John Muraski, Yan Chen, Yasuyuki Tsujita, Jason Wall, Christopher C. Glembotski, Erik Schaefer, Mary Beckerle, Mark A. Sussman
Takahiro Kato, John Muraski, Yan Chen, Yasuyuki Tsujita, Jason Wall, Christopher C. Glembotski, Erik Schaefer, Mary Beckerle, Mark A. Sussman
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Research Article Immunology

Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt

Abstract

This study delineates a mechanism for antiapoptotic signaling initiated by atrial natriuretic peptide (ANP) stimulation leading to elevation of cGMP levels and subsequent nuclear accumulation of Akt kinase associated with zyxin, a cytoskeletal LIM-domain protein. Nuclear targeting of zyxin induces resistance to cell death coincident with nuclear accumulation of activated Akt. Nuclear translocation of zyxin triggered by cGMP also promotes nuclear Akt accumulation. Additional supportive evidence for nuclear accumulation of zyxin-enhancing cardiomyocyte survival includes the following: (a) promotion of zyxin nuclear localization by cardioprotective stimuli; (b) zyxin association with phospho-Akt473 induced by cardioprotective stimuli; and (c) recruitment of zyxin to the nucleus by activated nuclear-targeted Akt as well as recruitment of Akt by nuclear-targeted zyxin. Nuclear accumulation of zyxin requires both Akt activation and nuclear localization. Potentiation of cell survival is sensitive to stimulation intensity with high-level induction by ANP or cGMP signaling leading to apoptotic cell death rather than enhancing resistance to apoptotic stimuli. Myocardial nuclear accumulation of zyxin and Akt responds similarly in vivo following treatment of mice with ANP or cGMP. Thus, zyxin and activated Akt participate in a cGMP-dependent signaling cascade leading from ANP receptors to nuclear accumulation of both molecules. Nuclear accumulation of zyxin and activated Akt may represent a fundamental mechanism that facilitates nuclear-signal transduction and potentiates cell survival.

Authors

Takahiro Kato, John Muraski, Yan Chen, Yasuyuki Tsujita, Jason Wall, Christopher C. Glembotski, Erik Schaefer, Mary Beckerle, Mark A. Sussman

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Nuclear accumulation of zyxin is antiapoptotic. TUNEL assay (A) of cultu...
Nuclear accumulation of zyxin is antiapoptotic. TUNEL assay (A) of cultured cardiomyocytes infected with adenoviruses expressing GFP, full-length zyxin (zyxin-w.t.), or nuclear-targeted zyxin for 2 hours followed by treatment with 1 μmol/l staurosporine to induce apoptosis. Results shown were derived from 3 separate experiments. (B) Apoptosis in cultured cardiomyocyte evaluated by DNA laddering. Adenoviruses expressing β-gal or zyxin as wild-type, GFP-conjugated full length (GFP), residues 1-322 (N-term), residues 349–542 (C-term), or NES-deleted residues 322–331 (NES). Apoptotic stimulation was initiated by overexpression of pyk2 kinase as previously described (35). Typical result is shown of 3 separate repetitions for the laddering experiment. (C) TUNEL assay of cultured cardiomyocytes shows protective effect of nuclear-targeted zyxin accumulation in response to apoptotic challenge by ANP (10–6 M) but lack of protection by ANP (10–9 M) in response to apoptotic challenge by full-length wild-type zyxin accumulation. Adenoviral vectors were used for expression of zyxin constructs with GFP expression shown as a control for effects of ANP treatments. *P < 0.01; **P < 0.05.