Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
BACKGROUND
Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction.


RESULTS
In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension.


CONCLUSIONS
Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.
Silberman
Gad A
GA
Department of Medicine (Division of Cardiology), Emory University School of Medicine, Atlanta, GA, USA.
Fan
Tai-Hwang M
TH
Liu
Hong
H
Jiao
Zhe
Z
Xiao
Hong D
HD
Lovelock
Joshua D
JD
Boulden
Beth M
BM
Widder
Julian
J
Fredd
Scott
S
Bernstein
Kenneth E
KE
Wolska
Beata M
BM
Dikalov
Sergey
S
Harrison
David G
DG
Dudley
Samuel C
SC
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D054144:Heart Failure, Diastolic / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism; D000099211:Phospholamban
D001708:Biopterins; D002135:Calcium-Binding Proteins; D003900:Desoxycorticosterone; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen; D007703:Peptidyl-Dipeptidase A; D013481:Superoxides; D000099211:Phospholamban; C003402:sapropterin