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Published on: June 15, 2018
Long noncoding RNA MCM3AP-AS1 attenuates sepsis-induced cardiomyopathy by improving inflammation, oxidative stress,
Xiangbi Nie1, Wu Deng1, Han Zhou1
1Department of Emergency, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, NanChang 330006, Jiangxi, China.
Abstract:
Oxidative stress and inflammation are highly important for sepsis-mediated myocardial damage. The long noncoding RNA (lncRNA) MCM3AP-AS1 is involved in inflammatory diseases, but its function in acute myocardial injury during sepsis has not been fully elucidated. LPS and cecal ligation and puncture (CLP) were used to construct in vitro and in vivo sepsis-induced myocardial damage models, respectively. qRT-PCR was used to evaluate alterations in MCM3AP-AS1 and miR-501-3p alterations. After the MCM3AP-AS1 and miR-501-3p knockdown or overexpression models were established, the viability, apoptosis, inflammation, oxidative stress, and mitochondrial function of the myocardial cells were examined. Dual luciferase activity assay, RNA immunoprecipitation, and fluorescence in situ hybridization (FISH) confirmed the correlation among MCM3AP-AS1, miR-501-3p, and CADM1. Previous studies revealed that MCM3AP-AS1 was downregulated in sepsis patients, myocardial cells treated with LPS, and in the CLP mouse sepsis model, whereas miR-501-3p expression was increased. MCM3AP-AS1 overexpression hampered myocardial damage mediated by LPS and abated inflammation, oxidative stress, and mitochondrial dysfunction in myocardial cells and THP-1 cells. In contrast, MCM3AP-AS1 knockdown or miR-501-3p overexpression promoted all the effects of LPS. In vivo, MCM3AP-AS1 overexpression increased the survival rate of CLP mice; ameliorated myocardial injury; decreased the levels of TNF-α, IL-1β, IL-6, iNOS, COX2, ICAM1, VCAM1, PGE2, and MDA; and increased the levels of SOD, GSH-PX, Nrf2, and HO-1. Mechanistic studies demonstrated that MCM3AP-AS1 acted as a competitive endogenous RNA to repress miR-501-3p, enhance CADM1 expression, and dampen STAT3/nuclear factor-kappaB (NF-κB) activation. MCM3AP-AS1 suppresses myocardial injury elicited by sepsis by mediating the miR-501-3p/CADM1/STAT3/NF-κB axis.
Insights
Long noncoding RNA MCM3AP-AS1 protects against sepsis-induced myocardial injury by regulating the miR-501-3p/CADM1 axis, reducing inflammation and oxidative stress.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Sepsis Research
Background:
- Sepsis-induced myocardial damage involves oxidative stress and inflammation.
- The role of long noncoding RNA MCM3AP-AS1 in sepsis-related heart injury requires further investigation.
Purpose of the Study:
- To elucidate the function of MCM3AP-AS1 in sepsis-induced myocardial injury.
- To investigate the molecular mechanism involving MCM3AP-AS1, miR-501-3p, and CADM1 in sepsis.
Main Methods:
- Established in vitro (LPS) and in vivo (CLP) sepsis models.
- Utilized qRT-PCR, knockdown/overexpression, dual luciferase assay, RNA immunoprecipitation, and FISH.
- Assessed myocardial cell viability, apoptosis, inflammation, oxidative stress, and mitochondrial function.
Main Results:
- MCM3AP-AS1 was downregulated, while miR-501-3p was upregulated in sepsis models.
- MCM3AP-AS1 overexpression protected against myocardial injury, reduced inflammation and oxidative stress.
- MCM3AP-AS1 repressed miR-501-3p, enhanced CADM1, and inhibited STAT3/NF-κB activation.
Conclusions:
- MCM3AP-AS1 functions as a protective factor against sepsis-induced myocardial injury.
- The MCM3AP-AS1/miR-501-3p/CADM1 axis modulates inflammatory and oxidative pathways via STAT3/NF-κB.
- MCM3AP-AS1 represents a potential therapeutic target for sepsis-related heart complications.
