醫學遺傳學及基因體學每月研討會 ─ Finding the Missing Link in Cardiovascular Medicine
楊鎧鍵 助理教授 (臺大藥理所 / 臺大醫院內科部主治醫師)
It has become increasingly clear that the transcription of the eukaryotic genome is far more pervasive and complex than previously appreciated. While the expression of messenger RNAs (mRNAs) and microRNAs (miRNAs) account for only ~1% of all transcribed species, up to 90% of the mammalian genome is transcribed as long non-coding RNAs (lncRNAs), a heterogeneous group of non-coding transcripts longer than 200 nucleotides. LncRNAs have been shown to be functional and involved in specific physiological and pathological processes through epigenetic, transcriptional and post-transcriptional mechanisms. While the roles of lncRNAs in human diseases including cancer and neurodegenerative disorders are beginning to emerge, it remains unclear how lncRNA expression and regulation contributes to the pathogenesis in most cardiovascular diseases.
Exploiting next-generation sequencing technology, we have recently demonstrated that lncRNAs are dynamically regulated in failing human heart and in response to hemodynamic unloading with left ventricular assist device (LVAD). Taking advantage of the approach of system biology, we have identified multiple lncRNAs that could play a critical role in the pathogenesis of heart failure (HF).
One of the hallmark pathological changes with HF is cardiac fibrosis. Excessive accumulation of extracellular matrix (ECM) resulted from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenecity. Current treatment options for cardiac fibrosis, however, are very limited. We have identified a fibroblast-enriched lncRNA, lnc-Fibrogen, which is dysregulated in failing heart and its expression levels are highly correlated with that of cardiac fibrosis genes. Lnc-Fibrogen is abnormally expressed in cardiac fibroblasts upon pro-fibrotic stimuli such as TGFβ. We have shown that lnc-Fibrogen is required for TGFβ-induced fibroblast activation and ECM gene production. Moreover, lnc-Fibrogen host gene TXNDC5, an ER resident protein with the enzyme activity of protein disulfide isomerase, is required for TGFβ-induced ECM protein, but not mRNA, upregulation. These data suggest a coordinated profibrotic function of lnc-Fibrogen and TXNDC5, as well as the critical roles of lnc-Fibrogen and TXNDC5 in the pathogenesis of cardiac fibrosis.
In addition to explore the molecular mechanisms via which lncRNAs contribute to cardiovascular diseases, we are also interested in using lncRNAs as biomarker for disease diagnosis and outcome prediction. Specifically, we are using RNASeq to profile cell-free, plasma lncRNAs in various diseases to identify candidate lncRNAs that could be sensitive and specific markers to detect the presence of diseases, to reflect the responses of treatment, and to predict the outcomes. In the presentation, we will discuss our recent findings in discovering plasma lncRNAs that could serve as predictors of adverse cardiovascular outcomes in patients with end-stage renal disease.