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

2021 ◽  
Author(s):  
Yang Xiao ◽  
Karen Yim ◽  
Hong Zhang ◽  
Diane Bakker ◽  
Rianne Nederlof ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Clinical Stage ◽  
Cardiac Ischemia ◽  
Oxidative Stress Marker ◽  
Thioredoxin System ◽  
Ldh Release

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.

scholarly journals Oxidative Stress-Associated Impairment of Proteasome Activity during Ischemia–Reperfusion Injury

2000 ◽  
Vol 20 (10) ◽  
pp. 1467-1473 ◽  
Author(s):  
Jeffrey N. Keller ◽  
Feng F. Huang ◽  
Hong Zhu ◽  
Jin Yu ◽  
Ye-Shih Ho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Proteasome Inhibition ◽  
Cerebral Ischemia Reperfusion ◽  
Proteasome Subunits ◽  
Cerebral Ischemia Reperfusion Injury

Numerous studies indicate a role for oxidative stress in the neuronal degeneration and cell death that occur during ischemia–reperfusion injury. Recent data suggest that inhibition of the proteasome may be a means by which oxidative stress mediates neuronal cell death. In the current study, the authors demonstrate that there is a time-dependent decrease in proteasome activity, which is not associated with decreased expression of proteasome subunits, after cerebral ischemia–reperfusion injury. To determine the role of oxidative stress in mediating proteasome inhibition, ischemia–reperfusion studies were conducted in mice that either overexpressed the antioxidant enzyme glutathione peroxidase [GPX 1(+)], or were devoid of glutathione peroxidase activity (GPX −/−). After ischemia–reperfusion, GPX 1(+) mice displayed decreased infarct size, attenuated neurologic impairment, and reduced levels of proteasome inhibition compared with either GPX −/− or wild type mice. In addition, GPX 1(+) mice displayed lower levels of 4-hydroxynonenal-modified proteasome subunits after ischemia–reperfusion injury. Together, these data indicate that proteasome inhibition occurs during cerebral ischemia–reperfusion injury and is mediated, at least in part, by oxidative stress.

scholarly journals DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

2014 ◽  
Vol 5 (2) ◽  
pp. e1082-e1082 ◽  
Author(s):  
R K Dongworth ◽  
U A Mukherjee ◽  
A R Hall ◽  
R Astin ◽  
S-B Ong ◽  
...  
Keyword(s):  
Cell Death ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Acute Cardiac Ischemia

scholarly journals Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα

2019 ◽  
Vol 317 (6) ◽  
pp. H1231-H1242 ◽  
Author(s):  
Kristofer J. Haushalter ◽  
Jan M. Schilling ◽  
Young Song ◽  
Mira Sastri ◽  
Guy A. Perkins ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Catalytic Subunit ◽  
Cardiac Ischemia ◽  
Regulatory Subunit ◽  
Type I ◽  
Subsarcolemmal Mitochondria ◽  
Pka Regulatory Subunit

Type I PKA regulatory α-subunit (RIα; encoded by the Prkar1a gene) serves as the predominant inhibitor protein of the catalytic subunit of cAMP-dependent protein kinase (PKAc). However, recent evidence suggests that PKA signaling can be initiated by cAMP-independent events, especially within the context of cellular oxidative stress such as ischemia-reperfusion (I/R) injury. We determined whether RIα is actively involved in the regulation of PKA activity via reactive oxygen species (ROS)-dependent mechanisms during I/R stress in the heart. Induction of ex vivo global I/R injury in mouse hearts selectively downregulated RIα protein expression, whereas RII subunit expression appears to remain unaltered. Cardiac myocyte cell culture models were used to determine that oxidant stimulus (i.e., H2O2) alone is sufficient to induce RIα protein downregulation. Transient increase of RIα expression (via adenoviral overexpression) negatively affects cell survival and function upon oxidative stress as measured by increased induction of apoptosis and decreased mitochondrial respiration. Furthermore, analysis of mitochondrial subcellular fractions in heart tissue showed that PKA-associated proteins are enriched in subsarcolemmal mitochondria (SSM) fractions and that loss of RIα is most pronounced at SSM upon I/R injury. These data were supported via electron microscopy in A-kinase anchoring protein 1 (AKAP1)-knockout mice, where loss of AKAP1 expression leads to aberrant mitochondrial morphology manifested in SSM but not interfibrillar mitochondria. Thus, we conclude that modification of RIα via ROS-dependent mechanisms induced by I/R injury has the potential to sensitize PKA signaling in the cell without the direct use of the canonical cAMP-dependent activation pathway. NEW & NOTEWORTHY We uncovered a previously undescribed phenomenon involving oxidation-induced activation of PKA signaling in the progression of cardiac ischemia-reperfusion injury. Type I PKA regulatory subunit RIα, but not type II PKA regulatory subunits, is dynamically regulated by oxidative stress to trigger the activation of the catalytic subunit of PKA in cardiac myocytes. This effect may play a critical role in the regulation of subsarcolemmal mitochondria function upon the induction of ischemic injury in the heart.

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