Document Detail


Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
MedLine Citation:
PMID:  20083682     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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.
Authors:
Gad A Silberman; Tai-Hwang M Fan; Hong Liu; Zhe Jiao; Hong D Xiao; Joshua D Lovelock; Beth M Boulden; Julian Widder; Scott Fredd; Kenneth E Bernstein; Beata M Wolska; Sergey Dikalov; David G Harrison; Samuel C Dudley
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-01-18
Journal Detail:
Title:  Circulation     Volume:  121     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-03-11     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  519-28     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Biopterin / analogs & derivatives,  metabolism,  therapeutic use
Calcium-Binding Proteins / metabolism
Desoxycorticosterone
Disease Models, Animal
Heart Failure, Diastolic / drug therapy,  etiology*,  metabolism*
Hypertension / chemically induced,  complications*,  metabolism*
Male
Mice
Mice, Inbred C57BL
Myocardium / metabolism
Nephrectomy
Nitric Oxide / metabolism*
Nitric Oxide Synthase / metabolism*
Oxygen / metabolism
Peptidyl-Dipeptidase A / metabolism
Superoxides / metabolism
Ventricular Dysfunction, Left / etiology,  metabolism
Grant Support
ID/Acronym/Agency:
5 F32 HL086232-02/HL/NHLBI NIH HHS; P01 HL058000/HL/NHLBI NIH HHS; P01 HL058000-11A15167/HL/NHLBI NIH HHS; R01 DK39777/DK/NIDDK NIH HHS; R01 DK51445/DK/NIDDK NIH HHS; R01 HL073753/HL/NHLBI NIH HHS; R01 HL085520/HL/NHLBI NIH HHS; R01 HL085520/HL/NHLBI NIH HHS; R01 HL085520-01A2/HL/NHLBI NIH HHS; R01 HL085558/HL/NHLBI NIH HHS; R01 HL79032/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/phospholamban; 11062-77-4/Superoxides; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 31C4KY9ESH/Nitric Oxide; 40GP35YQ49/Desoxycorticosterone; EC 1.14.13.39/Nitric Oxide Synthase; EC 3.4.15.1/Peptidyl-Dipeptidase A; S88TT14065/Oxygen
Comments/Corrections
Comment In:
Circulation. 2010 Nov 23;122(21):e558; author reply e559   [PMID:  21098456 ]
Circulation. 2010 Feb 2;121(4):484-6   [PMID:  20083685 ]

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