N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy

Abstract

S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca(2+) sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca(2+) ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca(2+) sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM.

N-Acetylcysteine Influence on Oxidative Stress and Cardiac Remodeling in Rats During Transition from Compensated Left Ventricular Hypertrophy to Heart Failure

“…Similarly, to our findings, NAC also reduced ERK and JNK phosphorylation [14, 46]. The antifibrotic effect of NAC was also observed in other models and organs [46-48].…”

“…More recently, NAC has been evaluated in experimental models of cardiac injury, particularly hypertrophic cardiomyopathy in which NAC reduced oxidative stress, reversed established cardiac hypertrophy and fibrosis, prevented cardiac systolic and diastolic dysfunction, and improved arrhythmogenic propensity [12, 14, 46]. Similarly, to our findings, NAC also reduced ERK and JNK phosphorylation [14, 46].…”

Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice

“…Recent studies further indicated that posttranslational modification of cMyBP-C is directly associated with diastolic dysfunction. Oxidative stress-induced S -glutathionylation of cMyBP-C induces Ca 2+ sensitization and a slowing of cross-bridge kinetics, leading to diastolic dysfunction [49, 50]. The phosphorylation of cMyBP-C by PKA and CaMKIIδ [51–53] has been implicated in regulation of diastolic function [19, 54].…”

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

“…Biophysical studies have revealed diverse mutation-induced alterations in sarcomeric protein function, which lead to abnormalities in Ca 2+ handling (7)(8)(9)(10)(11)(12), energy metabolism (13)(14)(15)(16)(17)(18) and/or oxidative stress (19)(20)(21). This has prompted the testing of L-type Ca 2+ channel blockers (e.g., diltiazem) (22,23), angiotensin II receptor antagonists (e.g., losartan) (24), antioxidants (e.g., N-acetylcysteine) (21,25,26), and metabolic modulators (perhexiline) (27) with success in preventing hypertrophy, fibrosis, and adverse cardiac remodeling in animal models. However, neither diltiazem (28), nor losartan (29,30), nor perhexiline (31) is able to prevent development of the cardiac phenotype in HCM patients.…”