Potential Role of mRNAs and LncRNAs in Chronic Intermittent Hypoxia Exposure-Aggravated Atherosclerosis

Abstract

Atherosclerosis is the pathological basis of cardiovascular disease. Obstructive sleep apnea (OSA) aggravates atherosclerosis, and chronic intermittent hypoxia (CIH) as a prominent feature of OSA plays an important role during the process of atherosclerosis. The mechanisms of CIH in the development of atherosclerosis remain unclear. In the current study, we used microarray to investigate differentially expressed mRNAs and long non-coding RNAs (lncRNAs) in aorta from five groups of ApoE −/− mice fed with a high-fat diet and exposed to various conditions: normoxia for 8 weeks, CIH for 8 weeks, normoxia for 12 weeks, CIH for 12 weeks, or CIH for 8 weeks followed by normoxia for 4 weeks. Selected transcripts were validated in aorta tissues and RT-qPCR analysis showed correlation with the microarray data. Gene Ontology analysis and pathway enrichment analysis were performed to explore the mRNA function. Bioinformatic analysis indicated that short-term CIH induced up-regulated mRNAs involved in inflammatory response. Pathway enrichment analysis of lncRNA colocalized mRNAs and lncRNA co-expressed mRNAs were performed to explore lncRNA functions. The up-regulated mRNAs, lncRNA co-localized mRNAs and lncRNA coexpressed mRNAs were significantly associated with protein processing in endoplasmic reticulum pathway in atherosclerotic vascular tissue with long-term CIH exposure, suggesting that differentially expressed mRNAs and lncRNAs play important roles in this pathway. Moreover, a mRNA-lncRNA co-expression network with 380 lncRNAs, 508 mRNAs and 3238 relationships was constructed based on the correlation analysis between the differentially expressed mRNAs and lncRNAs. In summary, our study provided a systematic perspective on the potential function of mRNAs and lncRNAs in CIH-aggravated atherosclerosis, and may provide novel molecular candidates for future investigation on atherosclerosis exposed to CIH.

Intermittent Hypoxia and Atherosclerosis: From Molecular Mechanisms to the Therapeutic Treatment

“…In a study that analyzed the differential expression of mRNAs and long noncoding RNAs in atherosclerotic vascular tissues of ApoE −/− mice, markedly fewer genes were significantly upregulated in mice exposed to CIH for 12 weeks than in mice exposed to CIH for 8 weeks, which leads to weakening of atherosclerotic vascular tissue. The specific mechanism involved was related to the abnormal expression of heat shock proteins caused by CIH via the endoplasmic reticulum protein processing pathway [ 139 ]. This study also showed that the long-term CIH exposure resulted in reduced mRNA expression of Rev-erb (a member of the nuclear receptor superfamily that is important for the regulation of immunity, metabolic function, and circadian rhythm) and exacerbated the development of atherosclerosis, suggesting that Rev-erb may be involved in the development of CIH-related AS and play an important role in it.…”

“…Oxidative Medicine and Cellular Longevity of heat shock proteins caused by CIH via the endoplasmic reticulum protein processing pathway [139]. This study also showed that the long-term CIH exposure resulted in reduced mRNA expression of Rev-erb (a member of the nuclear receptor superfamily that is important for the regulation of immunity, metabolic function, and circadian rhythm) and exacerbated the development of atherosclerosis, suggesting that Rev-erb may be involved in the development of CIHrelated AS and play an important role in it.…”

Role of epigenetic abnormalities and intervention in obstructive sleep apnea target organs

“…Moreover, the differential expression levels of lncRNAs and mRNAs in atherosclerotic vascular tissue of CIH-exposed mice were screened. Changes were mainly an enrichment in the pathway of protein processing in the endoplasmic reticulum, which could ultimately turn to heat shock proteins, and their functions in protein folding may account for CIH aggravating atherosclerosis [140] …”

“…Changes were mainly an enrichment in the pathway of protein processing in the endoplasmic reticulum, which could ultimately turn to heat shock proteins, and their functions in protein folding may account for CIH aggravating atherosclerosis. [140] Conclusions and future directions…”

An Update on Obstructive Sleep Apnea for Atherosclerosis: Mechanism, Diagnosis, and Treatment

“…Another report depicted the profiling of mRNAs and lncRNAs in the aorta when treated with IH. The description of this system may provide potential candidates for future research on IH-induced AS ( 46 ). In addition, its unique RNA was also explored to understand its function.…”