Role of Apoptosis Signal-Regulating Kinase-1-c-Jun NH₂-Terminal Kinase-p38 Signaling in Voltage-Gated K⁺Channel Remodeling of the Failing Heart: Regulation by Thioredoxin

Abstract

Abstractc-Jun NH 2 -terminal kinase ( JNK) and p38 kinase are key regulators of cardiac hypertrophy and apoptosis during pathological stress, but their role in regulating ion channels in the diseased heart is unclear. Thus, we compared the kinase profile and electrophysiological phenotype of the rat ventricle 6-8 weeks after myocardial infarction (MI). Molecular analyses showed that JNK and p38 activities were markedly increased in post-MI hearts, while parallel voltage-clamp studies in ventricular myocytes revealed a characteristic downregulation of transient outward K + current (I to ) density. When post-MI myocytes were treated with JNK or p38 inhibitors, I to density increased to control levels. Upregulation of I to was also elicited by insulin-like growth factor-1, which decreased JNK=p38 activity in post-MI hearts, and these changes were blocked by the thioredoxin (Trx) reductase inhibitor auranofin. Consistent with activation of JNK-p38 signaling, binding of apoptosis signal-regulating kinase-1 with Trx1 was also markedly decreased post-MI, and was reversed by insulin-like growth factor-1 in an auranofinsensitive manner. We conclude that expression of ventricular K + channels is redox regulated and that chronic impairment of the Trx system in the post-MI heart contributes to I to remodeling through sustained activation of apoptosis signal-regulating kinase-1-JNK-p38 signaling. The cardiac Trx system may thus be a novel therapeutic target to reverse or prevent ventricular arrhythmias in the failing heart. Antioxid. Redox Signal. 14, 25-35.

The PPARγ Agonist Protects Cardiomyocytes from Oxidative Stress and ApoptosisviaThioredoxin Overexpression

“…34) Moreover, it is markedly expressed in rCMCs and protects them from oxidative stress. 35,36) In this study, we found that RSG significantly decreased H 2 O 2 -induced oxidative stress, and this effect was dependent on its ability to activate PPAR. Our data also suggest that most of the antioxidative activity of RSG is determined by its ability to activate TRx.…”

Thioredoxin 1 Is Essential for Sodium Sulfide–Mediated Cardioprotection in the Setting of Heart Failure

“…In the heart, Trx1 plays a pro-survival role in response to stress by inhibiting ASK1 15 and modulating the nuclear localization of class II histone deacetylases (HDACs). 16 Therefore, subsequent experiments focused on these two downstream targets of Trx1.…”

“…28 Under normal conditions, ASK1 constantly forms an inactive complex with Trx1. However, in response to the oxidative stress following myocardial infarction, Trx1 releases ASK1 enabling it to phosphorylate Jnk and p38 15 , which ultimately leads to pathological LV structural and functional remodeling. 3 The findings of the current study support the hypothesis that activation of ASK1 contributes to the development of heart failure following myocardial infarction, as evidenced by the finding that the improvements in LV dilatation and function in response to Na 2 S therapy are associated with a suppression of the ASK1-Jnk/p38 pathway.…”

Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

“…It attenuated cardiac hypertrophy in aged mice (9), reduced infarct size after reperfusion in mice and rats (768,829), lowered inflammatory cell infiltration in rats (829), diminished severity of myocarditis (442), and protected against reperfusion-induced arrhythmias in isolated rat hearts (27). Recent studies related the protective effect against arrhythmias with Trx1-dependent regulation of expression of ventricular K + channels (429,444,760). Trx1 levels in blood and serum of patients with dilated cardiomyopathy, acute coronary syndrome, or chronic heart failure were higher compared with controls, which correlated to the severity of the diseases (335,392).…”