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Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.

ABSTRACT: GCN5L1 regulates mitochondrial protein acetylation, cellular bioenergetics, reactive oxygen species (ROS) generation, and organelle positioning in a number of diverse cell types. However, the functional role of GCN5L1 in the heart is currently unknown. As many of the factors regulated by GCN5L1 play a major role in ischemia-reperfusion (I/R) injury, we sought to determine if GCN5L1 is an important nexus in the response to cardiac ischemic stress. Deletion of GCN5L1 in cardiomyocytes resulted in impaired myocardial post-ischemic function and increased infarct development in isolated work-performing hearts. GCN5L1 knockout hearts displayed hallmarks of ROS damage, and scavenging of ROS restored cardiac function and reduced infarct volume in vivo. GCN5L1 knockdown in cardiac-derived AC16 cells was associated with reduced activation of the pro-survival MAP kinase ERK1/2, which was also reversed by ROS scavenging, leading to restored cell viability. We therefore conclude that GCN5L1 activity provides an important protection against I/R induced, ROS-mediated damage in the ischemic heart.

SUBMITTER: Manning JR

PROVIDER: S-EPMC6486843 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.

Manning Janet R JR Thapa Dharendra D Zhang Manling M Stoner Michael W MW Traba Javier J McTiernan Charles F CF Corey Catherine C Shiva Sruti S Sack Michael N MN Scott Iain I

Journal of molecular and cellular cardiology 20190215

GCN5L1 regulates mitochondrial protein acetylation, cellular bioenergetics, reactive oxygen species (ROS) generation, and organelle positioning in a number of diverse cell types. However, the functional role of GCN5L1 in the heart is currently unknown. As many of the factors regulated by GCN5L1 play a major role in ischemia-reperfusion (I/R) injury, we sought to determine if GCN5L1 is an important nexus in the response to cardiac ischemic stress. Deletion of GCN5L1 in cardiomyocytes resulted in ...[more]

PMID: 30776374

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Project description:ObjectiveRecruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Escherichia coli augmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain-containing adapter-inducing interferon-β) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model.ConclusionsCollectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.

Project description:p53 is a tumor suppressor protein with a very low content in the basal condition, but the content rapidly rises during stress conditions including ischemia-reperfusion. An increase in p53 content increases cardiac injury during ischemia-reperfusion. Since mitochondrial damage plays a key role in cardiac injury during ischemia-reperfusion, we asked if genetic ablation of p53 decreases cardiac injury by protecting mitochondria. Isolated, perfused hearts from cardiac specific p53 deletion or wild type underwent 25 min global ischemia at 37 °C and 60 min reperfusion. At the end of reperfusion, hearts were harvested for infarct size measurement. In separate groups, cardiac mitochondria were isolated at 30 min reperfusion. Time control hearts were buffer-perfused without ischemia. Compared to wild type, deletion of p53 improved cardiac functional recovery and decreased infarct size following ischemia-reperfusion. Oxidative phosphorylation was improved in p53 deletion mitochondria following ischemia-reperfusion compared to wild type. The net release of ROS generation from wild type but not in p53 deletion mitochondria was increased following ischemia-reperfusion. Peroxiredoxin 3 (PRDX 3) content was higher in p53 deletion than that in wild type, indicating that p53 deletion increases a key antioxidant. Ischemia-reperfusion led to increased spectrin cleavage (a marker of cytosolic calpain1 activation) in wild type but not in p53 deletion mice. Ischemia-reperfusion increased the truncation of mature AIF (apoptosis inducing factor, an indicator of mitochondrial calpain1 activation) in wild type but not in p53 deletion mice. The loss of cytochrome c from mitochondria was also decreased in p53 deletion following ischemia-reperfusion. Bcl-2 content was decreased in wild type but not in p53 deletion following reperfusion, suggesting that depletion of bcl-2 contributes to permeabilization of the mitochondrial outer membrane. Thus, deletion of p53 decreases cardiac injury by protecting mitochondria through attenuation of oxidative stress and calpain activation during ischemia-reperfusion.

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Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.

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Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.

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