Abstract 10665: Tetrahydrobiopterin Improves Diastolic Dysfunction by Reversing Changes in Myofilament Properties
Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that an important therapy may involve nitric oxide (NO), which enhances cardiac relaxation, generated by NO synthase (NOS), which requires the co-factor tetrahydrobiopterin (BH4). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH4 depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH4 ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction and BH4 supplement was treated for 7 days after developing diastolic dysfunction. Mice were assessed by echocardiography and diastolic dysfunction was restored by BH4 administration. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH4 treatment. Diastolic sarcomere length and relengthening were also restored to control by BH4 treatment. pCa50 for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH4 treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt (6.5±0.2) compared to sham, but increased after BH4 treatment (7.4±0.4, P<0.05). Cardiac MyBP-C glutathionylation increased in DOCA-salt (3.6±0.5-fold) compared to sham, but decreased with BH4 treatment (2.2±0.3-fold, P<0.01). MyBP-C glutathionylation correlated with the presence of diastolic dysfunction and tension. Our results demonstrate BH4 ameliorates diastolic dysfunction by increasing myosin ATPase rate and increasing tension cost. These changes are associated with S-glutathionylation of MyBP-C, providing evidence for regulation of cardiac relaxation by post-translational modifications of myofilament proteins.
- © 2012 by American Heart Association, Inc.