Abstract
Atherosclerotic cardio-cerebrovascular disease and death remain the leading cause of morbidity and mortality worldwide. Defective efferocytosis, the clearance of apoptotic cells by macrophages, is thought to lead to increased inflammation and necrotic core formation in atherosclerotic lesions. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here we show that lncRNA myocardial infarction associated transcript (MIAT) was markedly elevated in the serum of patients with symptoms of vulnerable atherosclerotic plaque and the macrophages of necrotic cores in an advanced atherosclerosis mouse model. MIAT knockdown attenuated atherosclerosis progression, reduced necrotic core size, and increased plaque stability in vivo. Furthermore, MIAT knockdown promoted clearance of apoptotic cells by macrophages in vivo and in vitro. Mechanistic studies revealed that MIAT acted as a micro RNA (miRNA) sponge to positively modulate the expression of anti-phagocytic molecule CD47 through sponging miR-149-5p. Together, these findings identified a macrophage MIAT/miR-149-5p /CD47 pathway as a key factor in the development of necrotic atherosclerotic plaques.
Highlights
Atherosclerotic plaque vulnerability has been identified as the major cause of the atherosclerotic cerebrovascular disease[1,2]
Myocardial infarction associated transcript (MIAT) was upregulated in symptomatic human atherosclerotic disease and in advanced mouse atherosclerosis Disease-associated long noncoding RNA (lncRNA) can often be detected in the circulation and may biologically influence the local disease process[7,8]
We first assessed whether the expression of MIAT was altered in atherosclerotic disease using quantitative reverse transcription polymerase chain reaction analysis of serum RNA extracted from the control group and atherosclerotic patients who had suffered either a transient ischemic attack or stroke or were asymptomatic
Summary
Atherosclerotic plaque vulnerability has been identified as the major cause of the atherosclerotic cerebrovascular disease[1,2]. Long noncoding RNAs (lncRNAs) belong to a class of non-protein-coding RNAs longer than 200 nucleotides involved in the epigenetic regulation by Myocardial infarction associated transcript (MIAT), termed as Gomafu in humans or Rncr[2] in mice, is a highly conserved mammalian lncRNA10,11. Recent reports based on the quantitative polymerase chain reaction (PCR) have indicated that MIAT is highly expressed in human carotid plaques and might be a potential diagnostic indicator in ischemic stroke[14,15]. These results suggest that MIAT may have potential roles in atherosclerotic cerebrovascular disease. In the current study we aimed to determine whether MIAT was a critical regulator of plaque vulnerability and to define the underlying molecular mechanisms
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