Key result
In isolated mouse hearts subjected to short-duration ischemia, 10 μM KH176m reduced infarct size and cell death compared to control, but protection was lost with prolonged ischemia.
Why the study?
To examine KH176m's potential to protect against acute cardiac ischemia-reperfusion injury, compare it with MPG, and determine whether protection depends on ischemia duration.
Does the redox modulator KH176m or the antioxidant MPG reduce cardiac ischemia-reperfusion injury in isolated mouse hearts?
Does the redox modulator KH176m or the antioxidant MPG reduce cardiac ischemia-reperfusion injury in isolated mouse hearts?
The antioxidant KH176m protects against short-duration, but not long-duration, cardiac ischemia-reperfusion injury in isolated mouse hearts, highlighting that antioxidant efficacy is critically dependent on ischemia duration.
Answers are grounded in this paper and cite their sources.
May protect against cardiac IRI in preclinical models; leaves open clinical translation for mitochondrial disease.
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.
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Xiao et al. (2021) studied Cardiac ischemia-reperfusion injury (n=89). KH176m vs. Saline was evaluated on Infarct size following short (20 min) ischemia (p=<0.05). In isolated mouse hearts subjected to short-duration ischemia, 10 μM KH176m reduced infarct size and cell death compared to control, but protection was lost with prolonged ischemia.
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