Abstract 14303: Chronic Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II by KN-93 Causes Regression of Cardiac Dysfunction in Rats With isoproterenol-induced Heart Failure
Background: Recent evidence indicates that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in heart failure (HF), contributing to electric, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for HF. However, the role and mechanism of chronic CaMKII inhibition in HF is unclear. We assessed the hypothesis that CaMKII inhibition with KN-93 improves cardiomyocyte function, [Ca2+]i regulation, and β-adrenergic reserve, thus limiting HF progression.
Methods: We compared sympathetic nervous system (SNS) activation, left ventricular (LV) and myocyte functional responses in 4 groups of SD rats (8/group) over 16 weeks (W), in control (C) and rats with HF induced by isoproterenol (ISO) (170 mg/kg sq for 2 days). At 12 W after ISO, HF animals were assigned to receive 4 W treatment with: placebo (saline); KN-92 (70 μg/kg/day sq via mini pump) or KN-93 (70 μg/kg/day sq via mini pump), respectively.
Results: Compared with C, ISO-treated rats had HF onset at 4 W after ISO injection and progressed to severe HF at 16 W with increased plasma NE (1364 vs 312 pg/ml), decreased ejection fraction (38% vs 63%) and LV contractility (EES, 0.8 vs 1.3 mmHg/μl). LV time constant of relaxation (τ) (17.7 vs 10.9 ms) increased, accompanied with significantly reductions in dL/dtmax (47%, 79 vs 150 μm/s), dR/dtmax (41%, 68 vs 116 μm/s) and decreased [Ca2+]i transient ([Ca2+]iT) (36%, 0.18 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10-8 M) was attenuated with significantly less increases in dL/dtmax (35% vs 80%) and [Ca2+]iT (18% vs 37%). The LV and myocyte dysfunction persisted in KN-92-treated HF group. In contrast, treatment with KN-93 significantly increased EES (1.32 mmHg/μl) and EF (62%), decreased τ (12.0 ms) and corrected the elevation of plasma NE (309 pg/ml). Importantly, basal myocyte contraction dL/dtmax (149 μm/s), relaxation dR/dtmax (108 μm/s) and [Ca2+]iT (0.26) improved, and ISO-induced increase in dL/dtmax (69%), dR/dtmax (67%), and [Ca2+]iT (36%) were significantly augmented.
Conclusion: Chronic CaMKII inhibition prevents HF-induced SNS activation and improves LV and intrinsic myocyte basal and β-AR stimulated contraction, relaxation and [Ca2+]iT, thus playing a salutary role in HF.
Author Disclosures: C. Cheng: None. Q. Shao: None. H. Cheng: None. M.F. Callahan: None. T. Li: None.
- © 2016 by American Heart Association, Inc.