Abstract
Sepsis is a life-threatening organ dysfunction caused by a host’s dysfunctional response to infection. As is known to all, septic heart disease occurs because pathogens invading the blood stimulate the activation of endothelial cells, causing a large number of white blood cells to accumulate and trigger an immune response. However, in severe sepsis, the hematopoietic system is inhibited, and there will also be a decline in white blood cells, at which time the autoimmune system will also be suppressed. During the immune response, a large number of inflammatory factors are released into cells to participate in the inflammatory process, which ultimately damages cardiac myocytes and leads to impaired cardiac function. N6-methyladenosine (m6A) is a common RNA modification in mRNA and non-coding RNA that affects RNA splicing, translation, stability, and epigenetic effects of some non-coding RNAs. A large number of emerging evidences demonstrated m6A modification had been involved in multiple biological processes, especially for sepsis and immune disorders. Unfortunately, there are limited results provided to analyze the association between m6A modification and sepsis-induced cardiovascular dysfunction (SICD). In this review, we firstly summarized current evidences on how m6A mediates the pathophysiological process in cardiac development and cardiomyopathy to emphasize the importance of RNA methylation in maintaining heart biogenesis and homeostasis. Then, we clarified the participants of m6A modification in extended inflammatory responses and immune system activation, which are the dominant and initial changes secondary to sepsis attack. After that, we deeply analyzed the top causes of SICD and identified the activation of inflammatory cytokines, endothelial cell dysfunction, and mitochondrial failure. Thus, the highlight of this review is that we systematically collected all the related potential mechanisms between m6A modification and SICD causes. Although there is lack of direct evidences on SICD, indirect evidences had been demonstrated case by case on every particular molecular mechanism and signal transduction, which require further explorations into the potential links among the listed mechanisms. This provides novel insights into the understanding of SICD.
Highlights
Sepsis is defined as a highly heterogeneous syndrome that is associated with a dysregulated systemic inflammatory host response to infection and causes organ dysfunction (Singer et al, 2016; Cecconi et al, 2018)
Septic heart disease occurs because pathogens invading the blood stimulate the activation of endothelial cells, cause accumulation of vast m6A in sepsisinduced cardiovascular dysfunction (SICD)
There is limited evidence available to analyze the association between m6A modification and SICD
Summary
Sepsis is defined as a highly heterogeneous syndrome that is associated with a dysregulated systemic inflammatory host response to infection and causes organ dysfunction (Singer et al, 2016; Cecconi et al, 2018). The RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level predominantly represented changes in structural plasticity (Berulava et al, 2020) These studies show the role of the regulation of m6A methylation in the occurrence and development of cardiomyopathy, highlighting the critical importance of this stress response mechanism for maintaining normal heart function. Cardiac dysfunction and cardiovascular collapse during sepsis result from increased levels of several cytokines and from increased production of nitric oxide (NO), which is cytotoxic and can form a complex by combining with cis-aconitase in the respiratory chain, mitochondrial respiratory chain complexes I and II, and the active site of key enzymes in DNA synthesis, destroying their activity and causing myocardium apoptosis, and mitochondrial failure in cardiomyocytes (CMs), which leads to further DNA damage and ATP depletion, resulting in secondary energy failure. Increased circulating serum levels of IL-6 were associated with the severity of illness and the degree of vasopressor requirement in patients with septic shock (Gamkrelidze et al, 2014)
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