Journal
CIRCULATION
Volume 121, Issue 4, Pages 519-U89Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.109.883777
Keywords
diastole; heart failure; nitric oxide; nitric oxide synthase
Funding
- National Institutes of Health (NIH) [R01 HL085520, R01 HL085558, R01 HL073753, R01 DK39777, R01 DK51445, 5 F32 HL086232-02, R01 HL79032]
- American Heart Association Established Investigator Award [0440164N]
- Veterans Affairs MERIT
- American Heart Association Scientist Development
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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 (BH4) 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 BH4, 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 BH4 (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH4 stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH4 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. BH4 may represent a possible treatment for diastolic dysfunction. (Circulation. 2010;121:519-528.)
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