Abstract
BackgroundThe link between cardiac diseases and cognitive deterioration has been accepted from the concept of “cardiogenic dementia”, which was proposed in the late 1970s. However, the molecular mechanism is unclarified.MethodsThe two animal models used in this study were cardiac-specific overexpression of microRNA-1-2 transgenic (Tg) mice and a myocardial infarction mouse model generated by left coronary artery ligation (LCA). First, we observed the microRNA-1 (miR-1) level and synaptic vesicles (SV) distribution in the hippocampus using in situ hybridization and transmission electron microscopy (TEM) and evaluated the expression of vesicle exocytosis related proteins by western blotting. Second, we used dual luciferase reporter assay as well as antagonist and miRNA-masking techniques to identify the posttranscriptional regulatory effect of miR-1 on the Snap25 gene. Third, FM1–43 staining was performed to investigate the effect of miR-1 on synaptic vesicle exocytosis. Lastly, we used GW4869 to inhibit the biogenesis and secretion of exosomes to determine the transportation effect of exosomes for miR-1 from the heart to the brain.ResultsCompared with the levels in age-matched WT mice, miR-1 levels were increased in both the hearts and hippocampi of Tg mice, accompanied by the redistribution of SVs and the reduction in SV exocytosis-related protein SNAP-25 expression. In vitro studies showed that SNAP-25 protein expression was down- or upregulated by miR-1 overexpression or inhibition, respectively, however, unchanged by miRNA-masking the 3’UTR of the Snap25 gene. SV exocytosis was inhibited by miR-1 overexpression, which could be prevented by co-transfection with an anti-miR-1 oligonucleotide fragment (AMO-1). The knockdown of miR-1 by hippocampal stereotaxic injection of AMO-1 carried by a lentivirus vector (lenti-pre-AMO-1) led to the upregulation of SNAP-25 expression and prevented SV concentration in the synapses in the hippocampi of Tg mice. The application of GW4869 significantly reversed the increased miR-1 level in the blood and hippocampi as well as reduced the SNAP-25 protein levels in the hippocampi of both Tg and LCA mice.ConclusionThe overexpression of miR-1 in the heart attenuated SV exocytosis in the hippocampus by posttranscriptionally regulating SNAP-25 through the transportation of exosomes. This study contributes to the understanding of the relationship between cardiovascular disease and brain dysfunction.
Highlights
The link between cardiac diseases and cognitive deterioration has been accepted from the concept of “cardiogenic dementia”, which was proposed in the late 1970s
Abnormal synaptic vesicle distribution in the hippocampi of cardiac-specific miR-1 overexpression Tg mice To observe whether the overexpression of miR-1 in the heart could induce synaptic pathological remodelling in the brain, a mouse line for the cardiac-specific overexpression of miR-1-2 driven by the α-myosin heavy chain (α-MHC) promoter was developed as described previously [26]
Using transmission electron microscopy (TEM) examination, we found that the total number of synaptic vesicles (SVs) in the whole presynaptic area of the hippocampus was significantly increased (Fig. 2c and d)
Summary
The link between cardiac diseases and cognitive deterioration has been accepted from the concept of “cardiogenic dementia”, which was proposed in the late 1970s. Whether miRNAs could mediate long-distance heart-brain communication and act as a link between heart disease and brain dysfunction is largely unknown, which would be very interesting. MicroRNA-1 (miR-1) is a muscle-enriched miRNA that presents a hundred-fold lower level in the brain than in the heart [17, 18]. Our previous study demonstrated the behavioural abnormalities in a cardiac-specific microRNA-1-2 (miR-1-2) overexpression transgenic (Tg) mouse model, which was associated with the downregulation of BDNF expression in the hippocampus [18]. A very recent study demonstrated that the overexpression of miR-1 in the heart could induce neuronal microtubule damage [19]. These studies revealed the potential of cardiac-originated miRNAs to regulate brain function. Clarifying the underlying biological significance of heart-brain communication mediated by miRNAs would provide a new insight into association to the prevention of brain dysfunction
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