Coronary artery diseases (CAD) and heart failure have high mortality rate in the world, although much progress has been made in this field in last two decades. There is still a clinical need for a novel diagnostic approach and a therapeutic strategy to decrease the incidence of CAD. MicroRNAs (miRNAs) are highly conserved noncoding small RNA molecules that regulate a large fraction of the genome by binding to complementary messenger RNA sequences, resulting in posttranscriptional gene silencing. Recent studies have shown that specific miRNAs are involved in whole stage of atherosclerosis, from endothelium dysfunction to plaque rupture. These findings suggest that miRNAs are potential biomarkers in early diagnosis and therapeutic targets in CAD. In the present review, we highlight the role of miRNAs in every stage of atherosclerosis, and discuss the prospects of miRNAs in the near future.
Background
Toll‐like receptor (
TLR
) 9 recognizes bacterial
DNA
, activating innate immunity, whereas it also provokes inflammation in response to fragmented
DNA
released from mammalian cells. We investigated whether
TLR
9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient (
Apoe
−/−
) mice.
Methods and Results
Tlr9
‐deficient
Apoe
−/−
(
Tlr9
−/−
Apoe
−/−
) mice and
Apoe
−/−
mice on a Western‐type diet received subcutaneous angiotensin
II
infusion (1000 ng/kg per minute) for 28 days. Angiotensin
II
increased the plasma level of double‐stranded DNA, an endogenous ligand of
TLR
9, in these mice. Genetic deletion or pharmacologic blockade of
TLR
9 in angiotensin II–infused
Apoe
−/−
mice attenuated atherogenesis in the aortic arch (
P
<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased
RNA
expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of
TLR
9 in bone marrow in
Tlr9
−/−
Apoe
−/−
mice promoted atherogenesis in the aortic arch (
P
<0.05). A
TLR
9 agonist markedly promoted proinflammatory activation of
Apoe
−/−
macrophages, partially through p38 mitogen‐activated protein kinase signaling. In addition, genomic
DNA
extracted from macrophages promoted inflammatory molecule expression more effectively in
Apoe
−/−
macrophages than in
Tlr9
−/−
Apoe
−/−
macrophages. Furthermore, in humans, circulating double‐stranded
DNA
in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction (
P
<0.05).
Conclusions
TLR
9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages.
TLR
9 may serve as a potential therapeutic target for atherosclerosis.
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