The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury

Abstract

Purpose Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m’s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

Reduction in mitochondrial ROS improves oxidative phosphorylation and provides resilience to coronary endothelium in non-reperfused myocardial infarction

“…We have recently reported paradoxical improvement and detrimental signaling, angiogenesis, and endothelial function with short-term versus long-term endothelium-specific NOX2 OE, respectively, in a transgenic animal model, highlighting the importance of EC mito-ROS homeostasis [ 49 , 50 ]. Since the finding that a short-term increase in NOX2-derived ROS results in the upregulation of MnSOD and angiogenesis, several studies have reported beneficial effects of MnSOD-mimetics on cardiac recovery and angiogenesis [ 15 , 19 , 66 ]. However, the mito-ROS scavenging agents used in those studies were not EC-specific and thus might have modulated mito-ROS of different cell types including cardiomyocytes, vascular smooth muscle cells, and fibroblasts.…”

Effects of a mitochondrial-acting drug on ischemia/reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and inflammatory cytokines in rat: Role of adenosine triphosphate-sensitive potassium channels

“…14 In line with our current results, the active metabolite of this drug has reduced IR-induced cardiac damages and corrected mitochondrial myopathy by modifying mitochondrial redox activity. 10 The protective effects of this drug have been dependent on the duration of ischemia. Previous studies have shown that this drug modifies the biological consequences of mitochondrial complex-1 dysfunction (seen in Leigh syndrome).…”

“…In the KH-receiving groups, the KH176 was intraperitoneally injected into rats at concentrations of 10 μM (KH10) and 50 μM (KH50), 10 min before establishing reperfusion. 10 The drug was prepared in 1% DMSO and the non-treated IR animals received the same volume of DMSO intraperitoneally. To inhibit mK-ATP channels, 5-Hydroxydecanoate (5HD) at a concentration of 5 μM was injected intraperitoneally 5 min before injection of KH176 at 50 μM.…”

“…7,9 In confirmation of this hypothesis, a recent study has shown that this drug increases prostaglandin E2 (PGE2) activity by acting on mitochondria and decreases MI outcomes by increasing its antioxidant power and decreasing inflammatory responses. 10 Therefore, considering the therapeutic potentials of this drug and also due to the involvement of mitochondrial dysfunction and inflammatory responses in the development and severity of ventricular arrhythmias following cardiac IR damage, in this study we decided to evaluate the effect of this drug on reperfusion-induced ventricular arrhythmias, cardiac mitochondrial function and pro-inflammatory cytokine production, and explore the role of mitochondrial ATP-dependent K-channels (mK-ATP) in these effects.…”

Impact of Cytochrome P450 Enzymes on the Phase I Metabolism of Drugs

“…Sonlicromanol (KH176, Figure 4) is an antioxidant agent targeting the thioredoxin redox systems [48]. Recently, it obtained an orphan drug designation for maternally inherited diabetes and deafness [49] and it is now in phase IIB clinical trials for mitochondrial disease treatments [50]. Sonlicromanol is a chiral drug [51] that, after metabolization, retains the same stereochemistry and it has been suggested to be a substrate for CYP3A4 [52,53].…”