Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt
Open Access
- 1 October 2005
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 115 (10), 2716-2730
- https://doi.org/10.1172/jci24280
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.Keywords
This publication has 67 references indexed in Scilit:
- Focal Adhesion Protein Zyxin Is a Mechanosensitive Modulator of Gene Expression in Vascular Smooth Muscle CellsHypertension, 2004
- Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK SignalingHypertension, 2004
- Targeted Disruption of the Murine zyxin GeneMolecular and Cellular Biology, 2003
- Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac RemodelingPublished by Elsevier BV ,2002
- Proliferative Actions of Natriuretic Peptides on Neuroblastoma CellsPublished by Elsevier BV ,2001
- Targeting of Zyxin to Sites of Actin Membrane Interaction and to the NucleusPublished by Elsevier BV ,2001
- Differing Metabolism and Bioactivity of Atrial and Brain Natriuretic Peptides in Essential HypertensionHypertension, 1996
- Suppression of hyperventilation-induced attack with infusion of B-type (brain) natriuretic peptide in patients with variant anginaAmerican Heart Journal, 1994
- Cardiovascular effects of intracoronary atrial natriuretic peptide administration in manAmerican Heart Journal, 1990
- Hemodynamic and renal effects of atrial natriuretic peptide in congestive heart failureThe American Journal of Cardiology, 1990