TY - JOUR
T1 - Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties
AU - Jeong, Euy Myoung
AU - Monasky, Michelle M.
AU - Gu, Lianzhi
AU - Taglieri, Domenico M.
AU - Patel, Bindiya G.
AU - Liu, Hong
AU - Wang, Qiongying
AU - Greener, Ian
AU - Dudley, Samuel C.
AU - Solaro, R. John
PY - 2013/3
Y1 - 2013/3
N2 - 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 cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring 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. Mice were divided into two groups that received control diet and two groups that received BH4 supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH4 treatment. Diastolic sarcomere length (DOCA-salt 1.70±0.01 vs. DOCA-salt+BH4 1.77±0.01μm, P4 0.08±0.01, P4 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 compared to sham, but increased after BH4 treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH4 treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH4 ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.
AB - 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 cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring 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. Mice were divided into two groups that received control diet and two groups that received BH4 supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH4 treatment. Diastolic sarcomere length (DOCA-salt 1.70±0.01 vs. DOCA-salt+BH4 1.77±0.01μm, P4 0.08±0.01, P4 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 compared to sham, but increased after BH4 treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH4 treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH4 ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.
KW - Ca sensitivity
KW - Deoxycorticosterone acetate (DOCA)-salt mice
KW - Diastolic heart failure
KW - MyBP-C
KW - Oxidative stress
KW - S-glutathionylation
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U2 - 10.1016/j.yjmcc.2012.12.003
DO - 10.1016/j.yjmcc.2012.12.003
M3 - Article
C2 - 23247392
AN - SCOPUS:84873140248
VL - 56
SP - 44
EP - 54
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 1
ER -