LncRNAs Stand as Potent Biomarkers and Therapeutic Targets for Stroke

More proof no one in stroke knows one damn thing about recovery.  Nothing will change until we get survivors in charge, including running hospitals.

LncRNAs Stand as Potent Biomarkers and Therapeutic Targets for Stroke

Junfen Fan^1,2, Madeline Saft³, Nadia Sadanandan³, Bella Gonzales-Portillo³, You Jeong Park³, Paul R. Sanberg³, Cesario V. Borlongan^3* and Yumin Luo^1,2,4*

• ¹Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
• ²Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China
• ³Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
• ⁴Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China

Stroke is a major public health problem worldwide with a high burden of neurological disability and mortality. Long noncoding RNAs (lncRNAs) have attracted much attention in the past decades because of their newly discovered roles in pathophysiological processes in many diseases. The abundance of lncRNAs in the nervous system indicates that they may be part of a complex regulatory network governing physiology and pathology of the brain. In particular, lncRNAs have been shown to play pivotal roles in the pathogenesis of stroke. In this article, we provide a review of the multifaceted functions of lncRNAs in the pathogenesis of ischemic stroke and intracerebral hemorrhage, highlighting their promising use as stroke diagnostic biomarkers and therapeutics. To this end, we discuss the potential of stem cells in aiding lncRNA applications in stroke.

Introduction

Ischemic stroke is primarily characterized by insufficient blood flow to the brain, whereas hemorrhagic stroke leads to bleeding in the brain, with both types of stroke accompanied by a multitude of biological processes including oxygen deprivation, inflammatory response, oxidative stress, neurotoxicity of excitatory amino acids, apoptosis and edema formation, eventually culminating to severe neurovascular damage (Sahota and Savitz, 2011; Ahad et al., 2020; Virani et al., 2020). Intravascular thrombolysis and mechanical thrombectomy have significantly improved the prognosis of patients with acute ischemic stroke (AIS; Hacke et al., 1995; Berkhemer et al., 2015). However, only a small proportion of patients can receive these two treatments in clinical scenarios due to the narrow therapeutic time window and a considerable incidence of intracranial hemorrhagic conversion (Fonarow et al., 2011; Powers et al., 2018). Little is known about the pathogenesis and treatment options of intracerebral hemorrhage. Surgical evacuation is the main therapeutic option for intracerebral hemorrhage (Gross et al., 2019). Although great efforts have been made in investigating the complex mechanism of stroke-induced neuronal death, there is still a lack of effective treatment for neurological deficits caused by stroke. Therefore, the discovery of new targets and biomarkers is of great significance for ischemic stroke and intracerebral hemorrhage therapy.

GRAPHICAL ABSTRACT

According to the Human Genome Project study, only a minor portion of the mammalian genome encodes the protein-coding transcriptome, whereas the vast majority (approximately 80%) is transcribed into non-coding RNAs (ncRNAs; Djebali et al., 2012). Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides without or with the ability to encode proteins, but occupy a large part of the transcriptional output (Anderson et al., 2015; Matsumoto et al., 2017; Kopp and Mendell, 2018). LncRNAs were primarily considered as the “noise” of genomic transcription and had no biological functions (Ponting et al., 2009). Mounting evidence illustrates that lncRNAs are essential regulators of various biological processes including cell differentiation, proliferation, and apoptosis, as well as diseases such as cancer, metabolic disorders, cardiovascular diseases, and neurological disorders (Kurian et al., 2015; Bhan et al., 2017; Andersen and Lim, 2018; Yang Q. et al., 2018). LncRNAs also participate in brain development, neuron function, and progression of neurodegenerative diseases (Wan et al., 2017). Recently, lncRNAs have been highlighted to be involved in the pathological process of stroke.

A microarray profiling study firstly showed that lncRNA expression changes in the cerebral cortex at multiple time-points of reperfusion following transient middle cerebral artery occlusion (MCAO) in the adult rat (Dharap et al., 2012). Thereafter, altered lncRNA expression profiles have been investigated in rodent focal cerebral ischemia models, ischemic stroke patients as well as in vitro cultured cells following oxygen and glucose deprivation/reoxygenation (OGD/R; Zhao et al., 2015; Zhang et al., 2016; Guo et al., 2018). Kim et al. (2019) investigated the expression pattern of lncRNA from two different intracerebral hemorrhage rat models. The aberrant expression of lncRNAs uncovered in stroke has led researchers to explore the potential roles and mechanisms of specific lncRNA in brain physiology and pathology. We and other groups are among the first to elaborate on the functional significance of individual lncRNA in ischemic stroke. A recent study showed that the expression of lncRNA MEG3 was significantly upregulated following ischemia in vitro and in vivo, and it mediates ischemic neuronal death by targeting the miR-21/PDCD4 signaling pathway (Yan et al., 2017). LncRNA MALAT1 exerted neuroprotective effects in the post-stroke cerebral microvasculature, resulting in reduced cerebral vascular and parenchymal damage (Zhang X. et al., 2017). Our group reported that compared with healthy controls, circulating lncRNA H19 levels were upregulated in patients with stroke. Knockdown of lncRNA H19 could decrease infarct volume, brain edema, and neuroinflammation by driving HDAC1-dependent M1 microglial polarization (Wang et al., 2017a). Moreover, lncRNA H19 induces cerebral ischemia-reperfusion injury via activation of autophagy through the DUSP5-ERK1/2 axis (Wang et al., 2017b). Taken together, these findings indicate that lncRNAs play multiple roles in the post-stroke brain and provide evidence for their importance in stroke pathophysiology.

To date, an increasing number of lncRNAs have been identified to be involved in the molecular processes of ischemic stroke and intracerebral hemorrhage cascade. Here, we provide a systematic and comprehensive summary of the existing knowledge of lncRNAs and stroke in hopes to further elucidate this new research area.