Abstract 19210: Enhanced Denitrosylation Mitigates Cardiac Hypertrophy and Dysfunction During Chronic Pressure Overload
Protein S-nitrosylation (SNO) is a post-translational modification of protein thiol, which is a major effector mechanism of nitric oxide (NO) signaling. Level of protein SNO is controlled by S-nitrosoglutathione reductase (GSNOR). Recently, we showed that GSNOR mitigates intracellular calcium overload and LV remodeling and dysfunction induced by chronic β-adrenergic receptor (AR) stimulation. To further explore the role of protein SNO in LV remodeling and heart failure, we examined impact of chronic pressure overload induced by transverse aortic constriction (TAC) on cardiac function and hypertrophy in wild-type (WT, n=12), GSNOR-deficient (GSNOR-/-, n=5) and GSNOR-transgenic (GSNOR-Tg, n=6) mice that overexpresses GSNOR restrictively in cardiomyocytes. Degree of LV hypertrophy and function was examined with serial echocardiography and postmortem examination 4 weeks after TAC. Before TAC, body weight, LV mass, and fractional shortening (FS) were similar in the three genotypes. TAC induced marked LV hypertrophy (LV mass; from 82±5 to 135±15mg, P<0.001) and dysfunction (FS; from 54±4 to 43±5%, P<0.001) in WT mice. GSNOR-deficiency markedly worsen LV hypertrophy (LV mass; from 84±6 to 177±15mg, P<0.001 vs before TAC and vs WT) and dysfunction (FS; from 51±2 to 21±6% in GSNOR-/-, P<0.001 vs before TAC and WT). In contrast, GSNOR-overexpression prevented the TAC-induced increase of LV mass (from 81±8 to 95±13mg, P=NS vs before TAC, P<0.001 vs WT and GSNOR-/-) and reduction of FS (from 51±3 to 45±4%, P=NS vs before TAC, P<0.001 vs GSNOR-/-). In conclusion, GSNOR prevents cardiac hypertrophy and dysfunction during chronic pressure overload. These results indicate that the manipulation of protein SNO levels may prove therapeutic in cardiac remodeling and heart failure.
Author Disclosures: N. Mori: None. S. Kai: None. P. Sips: None. T. Irie: None. F. Ichinose: None.
- © 2016 by American Heart Association, Inc.