Regulation of VASP phosphorylation in cardiac myocytes: differential regulation by cyclic nucleotides and modulation of protein expression in diabetic and hypertrophic heart
- 1 November 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 297 (5), H1697-H1710
- https://doi.org/10.1152/ajpheart.00595.2009
Abstract
Vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cyclic nucleotide-dependent kinases that has been implicated in cardiac pathology, yet many aspects of VASP's molecular regulation in cardiomyocytes are incompletely understood. In these studies, we explored the role of VASP, both in signaling pathways in isolated murine myocytes, as well as in a model of cardiac hypertrophy in VASPnullmice. We found that the β-adrenergic agonist isoproterenol promotes the rapid and reversible phosphorylation of VASP at Ser157 and Ser239. Forskolin and the cAMP analog 8-(4-chlorophenylthio)-cAMP promote a similar pattern of VASP phosphorylation at both sites. The effects of isoproterenol are blocked by atenolol and by compound H-89, an inhibitor of the cAMP-dependent protein kinase. By contrast, phosphorylation of VASP only at Ser239 is seen following activation of particulate guanylate cyclase by atrial natriuretic peptide, or following activation of soluble guanylate cyclase by sodium nitroprusside, or following treatment of myocytes with cGMP analog. We found that basal and isoproterenol-induced VASP phosphorylation is entirely unchanged in cardiomyocytes isolated from either endothelial or neuronal nitric oxide synthase knockout mice. In cardiomyocytes isolated from diabetic mice, only basal VASP phosphorylation is increased, whereas, in cells isolated from mice subjected to ascending aortic constriction (AAC), we found a significant increase in basal VASP expression, along with an increase in VASP phosphorylation, compared with cardiac myocytes isolated from sham-operated mice. Moreover, there is further increase in VASP phosphorylation in cells isolated from hypertrophic hearts following isoproterenol treatment. Finally, we found that VASPnullmice subjected to transverse aortic constriction develop cardiac hypertrophy with a pattern similar to VASP+/+mice. Our findings establish differential receptor-modulated regulation of VASP phosphorylation in cardiomyocytes by cyclic nucleotides. Furthermore, these studies demonstrate for the first time that VASP expression is upregulated in hypertrophied heart.Keywords
This publication has 42 references indexed in Scilit:
- Nitric oxide synthase 3AfCS-Nature Molecule Pages, 2009
- Atrial Natriuretic Peptide-initiated cGMP Pathways Regulate Vasodilator-stimulated Phosphoprotein Phosphorylation and Angiogenesis in Vascular EndotheliumPublished by Elsevier BV ,2008
- Integrin signalling: The tug-of-war in heart hypertrophyCardiovascular Research, 2006
- Effect of a Cleavage-Resistant Collagen Mutation on Left Ventricular RemodelingCirculation Research, 2003
- Role of vasodilator‐stimulated phosphoprotein in protein kinase A‐induced changes in endothelial junctional permeabilityThe FASEB Journal, 2002
- Phosphorylation of the Vasodilator-stimulated Phosphoprotein Regulates Its Interaction with ActinPublished by Elsevier BV ,2000
- Regulation of Human Endothelial Cell Focal Adhesion Sites and Migration by cGMP-dependent Protein Kinase IPublished by Elsevier BV ,2000
- Regulation by cAMP of Post-translational Processing and Subcellular Targeting of Endothelial Nitric-oxide Synthase (Type 3) in Cardiac MyocytesPublished by Elsevier BV ,1997
- Purification of a vasodilator‐regulated phosphoprotein from human plateletsJBIC Journal of Biological Inorganic Chemistry, 1989
- Evaluation of the isolated perfused heart of mice, with special reference to vasoconstriction caused by intracoronary acetylcholineJournal of Pharmacological Methods, 1983