Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling.
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 Ser(239) in 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.
Gill
Robert M
RM
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Braz
Julian C
JC
Jin
Najia
N
Etgen
Gary J
GJ
Shen
Weiqun
W
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
D010750:Phosphoproteins; D012333:RNA, Messenger; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases; D005996:Nitroglycerin; D006152:Cyclic GMP; D000109:Acetylcholine; D001920:Bradykinin