Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling
- 1 June 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 292 (6), H2782-H2790
- https://doi.org/10.1152/ajpheart.00831.2006
Abstract
In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3–4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3–4 wk after the development of CHF, in which left ventricular contractile function was restored by 80–90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser239in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.Keywords
This publication has 30 references indexed in Scilit:
- The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: Complex post-transcriptional regulation of the components of the CK systemJournal of Molecular and Cellular Cardiology, 2005
- Bradykinin‐induced, endothelium‐dependent responses in porcine coronary arteries: involvement of potassium channel activation and epoxyeicosatrienoic acidsBritish Journal of Pharmacology, 2005
- Regulation of Vasodilator-stimulated Phosphoprotein Phosphorylation and Interaction with Abl by Protein Kinase A and Cell AdhesionJournal of Biological Chemistry, 2002
- Reduced coronary vasodilator responses to amlodipine in pacing-induced heart failure in conscious dogs: role of nitric oxideBritish Journal of Pharmacology, 2002
- Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxideNature, 2002
- Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin StimulationJournal of Biological Chemistry, 2001
- Increased Nitrovasodilator Sensitivity in Endothelial Nitric Oxide Synthase Knockout MiceHypertension, 2000
- Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3′,5′-Monophosphate Kinase IThe Journal of Experimental Medicine, 1999
- Coronary flow reserve in patients with dilated cardiomyopathyAmerican Heart Journal, 1993
- The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholineNature, 1980