Permissive role of AMPK and autophagy in adiponectin deficiency-accentuated myocardial injury and inflammation in endotoxemia

Ren, Jun; Xu, Xihui; Wang, Qiurong; Ren, Sidney Y.; Dong, Maolong; Zhang, Yingmei

doi:10.1016/j.yjmcc.2016.02.002

Cited by 52 publications

(39 citation statements)

References 63 publications

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“…This may indicate that LPS can stimulate severe autophagy, which is reported in previous studies [27]. A study showed that the a maladaptive role for autophagy in hearts subjected to LPS challenge [28]. Our data suggested that LPS challenge-induced myocardial autophagy is an adaptive response as evidenced by the favorable response from A769662 against LPS-induced cardiac injury which is expected to stimulate AMPK.…”

Section: Discussionsupporting

confidence: 81%

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Zhang

Zhao

Quan

et al. 2017

Biochemical and Biophysical Research Communications

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AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Cα. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis.

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Section: Discussionsupporting

confidence: 81%

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

Zhang

Zhao

Quan

et al. 2017

Biochemical and Biophysical Research Communications

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“…Despite the advance in medical technology and clinical management of sepsis (Ren & Wu, ; Stanzani, Duchen, & Singer, ), targeted therapy is still dismal for septic cardiomyopathy. Evidence from our lab and others has demonstrated a major role for endotoxin lipopolysaccharides (LPS) released from Gram‐negative bacteria in the inflammatory response and cardiovascular homeostasis in sepsis (Pfalzgraff & Weindl, ; Ren et al, ; Zhang et al, ). Although antioxidants (such as metallothionein, insulin‐like growth factor I and catalase), mitochondrial protein aldehyde dehydrogenase (ALDH2) and ER chaperones have shown some promise in the treatment of septic cardiomyopathy (Ceylan‐Isik et al, ; Durand et al, ; Pang, Peng et al, ; Turdi et al, ), clinical validation has not been consolidated for antioxidants and mitochondrial drugs in sepsis and septic hearts.…”

Section: Introductionmentioning

confidence: 99%

“…CD74 is a non‐polymorphic type II transmembrane glycoprotein, participating in T‐cell and B‐cell development, dendritic cell motility and macrophage inflammation in inflammatory diseases including liver fibrosis, diabetes mellitus, systemic lupus erythematosus and Alzheimer disease (Su, Na, Zhang, & Zhao, ). Given the important role of autophagy, oxidative stress and inflammation in septic hearts (Ren et al, ; Sun et al, ; Sun, Cai, & Zang, ), levels of autophagy, O 2 − production, apoptosis and proinflammatory markers were monitored in WT and Cd74 −/− mice challenged with LPS. Levels of key autophagy regulatory molecules including Akt, AMP‐dependent protein kinase (AMPK) and mTOR were evaluated in murine hearts.…”

Section: Introductionmentioning

confidence: 99%

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Luo

Fan

Yang

et al. 2020

British J Pharmacology

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Background and Purpose Lipopolysaccharides (LPS), an outer membrane component of Gram‐negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF‐CD74 in septic cardiomyopathy. Experimental Approach This study evaluated the impact of CD74 ablation on endotoxaemia‐induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. Key Results Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2− production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down‐regulated Skp2, an F‐box component of Skp1/Cullin/F‐box protein‐type ubiquitin ligase, while up‐regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP‐LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS‐induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5‐AzaC ameliorated LPS‐induced GFP‐LC3B formation and cardiomyocyte contractile dysfunction. Conclusion and Implications Our data suggested that CD74 ablation protected against LPS‐induced cardiac anomalies, O2− production, inflammation and apoptosis through suppression of autophagy in a Skp2‐SUV39H1‐mediated mechanism.

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“…Inflammation is a key regulator for autophagy. An increase in autophagy in response to inflammatory signals such as TNF‐α is also well‐known . Yuan et al reported that LPS and TNF‐α both induce autophagy of cardiomyocytes in vitro and in vivo, and enhanced autophagy by rapamycin protect against LPS‐mediated myocyte apoptsosis .…”

Section: Discussionmentioning

confidence: 99%

Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Wang

Guo

Ding

et al. 2018

JAHA

194

129

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BackgroundThere is evidence for inflammation, autophagy, and apoptosis in the ischemic heart. Autophagy is a physiologic process for tissue survival. Apoptosis, on the other hand, is a mechanism that serves to clear the debris in the setting of tissue injury. The balance between autophagy and apoptosis may be important in cell survival and cardiac function.Methods and ResultsWe examined the interplay of inflammation and myocyte autophagy and apoptosis during the ischemic process. We subjected mice to total left coronary artery ligation and studied these animals for up to 4 weeks. The inflammatory (tumor necrosis factor [TNF]‐α, monocyte chemoattractant protein‐1, interleukin‐6, and interleukin‐1β) and autophagic signals (light chain‐3 and beclin‐1) were strongest during the first week and then began to decline. However, the apoptotic signals peaked at week 2 after left coronary artery ligation, and the elevated levels persisted until the end of the fourth week. To elucidate the role of inflammation in the regulation of myocyte autophagy and apoptosis, we administered TNF‐α inhibitor (CAS1049741‐03‐8, Millipore, Burlington, MA) to the mice daily during the first week of myocardial infarction. Anti‐TNF‐α therapy reduced the levels of inflammatory cytokines and the inflammatory cell infiltration in and around the infarct area. However, cardiac function measured by echocardiography (fractional shortening and ejection fraction) worsened with anti‐TNF‐α therapy. More importantly, application of TNF‐α inhibitor markedly inhibited autophagy and promoted myocyte apoptosis in the border zone.ConclusionsThese observations suggest that inflammatory response may be protective in the early stage of the myocardial infarction through stimulation of myocyte autophagy. Anti‐inflammatory treatment early after coronary occlusion may have an adverse effect.

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Permissive role of AMPK and autophagy in adiponectin deficiency-accentuated myocardial injury and inflammation in endotoxemia

Cited by 52 publications

References 63 publications

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

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