Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction

Gad A. Silberman, Tai-Hwang 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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)519-528
Number of pages10
JournalCirculation
Volume121
Issue number4
DOIs
StatePublished - Feb 1 2010

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Nitric Oxide Synthase
Nitric Oxide
sepiapterin reductase
Hypertension
Blood Vessels
Hydralazine
Desoxycorticosterone
Cardiomegaly
Peptidyl-Dipeptidase A
Nephrectomy
Cardiac Myocytes
Superoxides
Acetates
Heart Failure
phospholamban

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Silberman, G. A., Fan, T-H., Liu, H., Jiao, Z., Xiao, H. D., Lovelock, J. D., ... Dudley, S. C. (2010). Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation, 121(4), 519-528. https://doi.org/10.1161/CIRCULATIONAHA.109.883777

Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. / Silberman, Gad A.; Fan, Tai-Hwang; Liu, Hong; Jiao, Zhe; Xiao, Hong D.; Lovelock, Joshua D.; Boulden, Beth M.; Widder, Julian; Fredd, Scott; Bernstein, Kenneth E.; Wolska, Beata M.; Dikalov, Sergey; Harrison, David G.; Dudley, Samuel C.

In: Circulation, Vol. 121, No. 4, 01.02.2010, p. 519-528.

Research output: Contribution to journalArticle

Silberman, GA, Fan, T-H, Liu, H, Jiao, Z, Xiao, HD, Lovelock, JD, Boulden, BM, Widder, J, Fredd, S, Bernstein, KE, Wolska, BM, Dikalov, S, Harrison, DG & Dudley, SC 2010, 'Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction', Circulation, vol. 121, no. 4, pp. 519-528. https://doi.org/10.1161/CIRCULATIONAHA.109.883777
Silberman, Gad A. ; Fan, Tai-Hwang ; Liu, Hong ; Jiao, Zhe ; Xiao, Hong D. ; Lovelock, Joshua D. ; Boulden, Beth M. ; Widder, Julian ; Fredd, Scott ; Bernstein, Kenneth E. ; Wolska, Beata M. ; Dikalov, Sergey ; Harrison, David G. ; Dudley, Samuel C. / Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. In: Circulation. 2010 ; Vol. 121, No. 4. pp. 519-528.
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AU - Silberman, Gad A.

AU - Fan, Tai-Hwang

AU - Liu, Hong

AU - Jiao, Zhe

AU - Xiao, Hong D.

AU - Lovelock, Joshua D.

AU - Boulden, Beth M.

AU - Widder, Julian

AU - Fredd, Scott

AU - Bernstein, Kenneth E.

AU - Wolska, Beata M.

AU - Dikalov, Sergey

AU - Harrison, David G.

AU - Dudley, Samuel C.

PY - 2010/2/1

Y1 - 2010/2/1

N2 - 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.

AB - 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.

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JF - Circulation

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