Mitochondrial Injury and Targeted Intervention in Septic Cardiomyopathy

Tan, Ying; Chen, Sainan; Zhong, Jian‐Jiang; Ren, Jun; Dong, Maolong

doi:10.2174/1381612825666190708155400

Cited by 35 publications

(26 citation statements)

References 89 publications

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“…Septic cardiomyopathy represents a severe form of multi‐organ anomalies in sepsis, leading to unfavourable changes in cardiac structure and function including dilated ventricles, impaired cardiac contractility and reduced cardiac output (Arfaras‐Melainis et al, ; Ceylan‐Isik et al, ; Pang, Zheng et al, ; Ren & Wu, ; Tan, Chen, Zhong, Ren, & Dong, ; Turdi et al, ; Zhang et al, ). Patients with sepsis commonly develop septic cardiomyopathy enroute to cardiogenic shock, contributing to a high mortality rate of ~70–90% in sepsis (Merx & Weber, ; Ren & Wu, ; Rudiger & Singer, ).…”

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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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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“…Inflammation response occurs as a result of increased pro-inflammatory and/or decreased antiinflammatory mediators, promoting acute or chronic pathological conditions (Ren and Wu, 2006;Tan et al, 2019). Chronic inflammation has a central and inciting role in the development of a wide variety of disorders.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Bioavailability of Boswellic Acid by Piper longum: A Computational and Pharmacokinetic Study

Vijayarani¹,

Govindarajulu

Ramesh

et al. 2020

Front. Pharmacol.

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Chronic inflammation is a key culprit factor in the onset and progression of several diseases. Novel and pharmacologically effective therapeutic approaches are needed for new treatment remedy or improved pharmacokinetics and pharmacodynamics for existing synthetic drugs, in particular natural products. Boswellic acids are well-known natural products, with capacity to effectively retard inflammation without severe adverse effects. However, the therapeutic use of Boswellic acids are greatly hindered by its poor pharmacokinetic properties. Co-administration strategies that facilitate the oral absorption and distribution of Boswellic acids should lead to a safe and more effective use of this product prophylactically and therapeutically in inflammatory disorders. In this study, we examined the effect of Piper longum extract on the absorption and bioavailability of Boswellic acid in rabbits. In addition, we further explored computational pharmacodynamic interactions between Piper longum and Boswellic acid. Piper longum extract at 2.5 and 10 mg/kg, increased the bioavailability of Boswellic acid (p < 0.05). Based on our drug-based computational modeling, cytochrome P450 (CYP450)-mediated mechanism was involved in increased bioavailability. These findings confirmed that Piper longum with Boswellic acid may be administered orally together for effective therapeutic efficacy. Thus, our studies support the application of Piper longum with Boswellic acid as a novel therapeutic avenue in diseases associated with inflammation.

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“…Cardiomyocytes also respond to sepsis during the early stage, which is closely associated with disease prognosis. In particular, SIc, which is a highly monitored disease in the intensive care unit, is characterized by myocardial contractile function impairment, cardiac enlargement, decreased ejection fraction, poor response to volumetric load contraction and decreased peak contraction pressure/end-systolic volume ratio (27,28). Therefore, the pathophysiological mechanism of SIc has been the focus of studies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR‑101‑3p protects against sepsis‑induced myocardial injury by inhibiting MAPK and NF‑κB pathway activation via the upregulation of DUSP1

Tang

Chen

et al. 2021

Int J Mol Med

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Numerous studies have found that microRNAs (miRNAs or miRs) are aberrantly expressed when sepsis occurs. The present study aimed to investigate the role of miR-101-3p in sepsis-induced myocardial injury and to elucidate the underlying mechanisms. Models of myocardial injury were established both in vivo and in vitro . The results revealed that miR-101-3p was upregulated in the serum of patients with sepsis-induced cardiomyopathy (SIC) and positively correlated with the levels of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α). Subsequently, rats were treated with miR-101-3p inhibitor to suppress miR-101-3p and were then exposed to lipopolysaccharide (LPS). The results revealed that LPS induced marked cardiac dysfunction, apoptosis and inflammation. The inhibition of miR-101-3p markedly attenuated sepsis-induced myocardial injury by attenuating apoptosis and the expression of pro-inflammatory cytokines. Mechanistically, dual specificity phosphatase-1 (DUSP1) was found to be a functional target of miR-101-3p. The downregulation of miR-101-3p led to the overexpression of DUSP1, and the inactivation of the MAPK p38 and NF-κB pathways. Moreover, blocking DUSP1 by short hairpin RNA against DUSP1 (sh-DUSP1) significantly reduced the myocardial protective effects mediated by the inhibition of miR-101-3p. Collectively, the findings of the present study demonstrate that the inhibition of miR-101-3p exerts cardioprotective effects by suppressing MAPK p38 and NF-κB pathway activation, and thus attenuating inflammation and apoptosis dependently by enhancing DUSP1 expression.

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Mitochondrial Injury and Targeted Intervention in Septic Cardiomyopathy

Cited by 35 publications

References 89 publications

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

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

Enhanced Bioavailability of Boswellic Acid by Piper longum: A Computational and Pharmacokinetic Study

Inhibition of miR‑101‑3p protects against sepsis‑induced myocardial injury by inhibiting MAPK and NF‑κB pathway activation via the upregulation of DUSP1

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