Long Noncoding RNAs in Pathological Cardiac Remodeling: A Review of the Update Literature

Abstract

Cardiac remodeling is a self-regulatory response of the myocardium and vasculature under the stressful condition. Cardiomyocytes (CMs), vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and cardiac fibroblasts (CFs) are all involved in this process, characterized by change of morphological structures and mechanical/chemical activities as well as metabolic patterns. Despite current development of consciousness, the control of cardiac remodeling remains unsatisfactory, and to further explore the underlying mechanism and seek the optimal therapeutic targets is still the urgent need in clinical practice. It is now emerging that long noncoding RNAs (lncRNAs) play key regulatory roles in these adverse responses: lncRNA TUG1, AK098656, TRPV1, GAS5, Giver, and Lnc-Ang362 have been indicated in hypertension-related vascular remodeling, H19, TUG1, UCA1, MEG3, APPAT, and lincRNA-p21 in atherosclerosis (AS), and HIF1A-AS1 and Lnc-HLTF-5 in aortic aneurysm (AA). In addition, Neat1, AK139328, APF, CAIF, AK088388, CARL, MALAT1, HOTAIR, XIST, and NRF are involved in postischemia myocardial remodeling, while Mhrt, Chast, CHRF, ROR, H19, Plscr4, and MIAT are involved in myocardial hypertrophy, and MALAT1, wisper, MEG3, and H19 are involved in extracellular matrix (ECM) reconstitution. Signaling to specific miRNAs by acting as endogenous sponge (ceRNA) was the main form that regulates the target gene expression during cardiac remodeling. This review will underline the updates of lncRNAs and lncRNA-miRNA interactions in maladaptive remodeling and also cast light on their potential roles as therapeutic targets, hoping to provide supportive background for following research.

Analysis of multi-factor regulated network and different clusters in hypertrophic obstructive cardiomyopathy

“…In vivo experiments revealed that knockdown of XIST can inhibit the myocardial cell apoptosis in acute myocardial infarction rat model by regulating miR-449 (Zhang et al, 2019). Besides, H19 has been identi ed as a regulator that targets PPARα of cardiac hypertrophy (Liu et al, 2016;Zhou et al, 2019). The results showed that XIST, MALAT1 and H19 possibly regulated other miRNAs involved in cardiac hypertrophy, such as miR-15b (Ooi et al, 2014), miR-19b (Li et al, 2019) and miR-29b (Yang et al, 2020) in our research.…”

Preliminary study on the mechanism of long noncoding RNA SENCR regulating the proliferation and migration of vascular smooth muscle cells

“…Studies have shown that, like miRNAs, some lncRNAs are involved in the development of various cardiovascular diseases (Kok & Baker, 2019; Zhou et al, 2019). For example, MIAT (Z. M. Ye et al, 2019) and MALAT1 (Cremer et al, 2019) has been shown involved in the development of AS.…”

Long noncoding RNA NEAT1 correlates with higher disease risk, worse disease condition, decreased miR‐124 and miR‐125a and predicts poor recurrence‐free survival of acute ischemic stroke

“…Furthermore, we also explored the association of lncRNA NEAT1 expression with disease condition as well as inflammation level in patients with AIS, and we observed that lncRNA NEAT1 high expression was associated with increased NIHSS score, raised CRP level, elevated pro‐inflammatory cytokines levels (including TNF‐α, IL‐6, IL‐8, and IL‐22), and reduced anti‐inflammatory cytokine level (IL‐10) in patients with AIS. The possible reasons for these results might be as follows: (a) lncRNA NEAT1 might enhance the dysfunction of cerebral microglial cells through Wnt/β‐catenin signaling pathway, thus, it contributed to impairing the normal cerebrovascular physiology that led to advanced disease severity, and consequently, elevated NIHSS score was found in lncRNA NEAT1 high expression patients with AIS; (b) lncRNA NEAT1 might induce the loss of motor neurons and lead to the devastating neurodegenerative disorder, thus aggravated the abnormal cognitive deficits and functional activities of patients with AIS and increased the NIHSS score; (c) lncRNA NEAT1 promoted intima thickening or vascular occlusion by modulating the phenotype conversion of vascular smooth muscle cells, together with excessive apoptosis of epithelial cells, which might enhance the atherosclerotic lesion and aggravate the severity of AIS, thus lncRNA NEAT1 correlated with increased NIHSS score; (d) lncRNA NEAT1 might enhance the reactive oxygen species (ROS) level to disturb the normal initiation of inflammatory cascades, which further induced excess production of inflammatory cytokines, and thus, it led to increased levels of inflammatory factors (including CRP, TNF‐α, IL‐6, IL‐8, and IL‐22) as well as reduced anti‐inflammatory cytokine level in patients with AIS …”

“…Furthermore, the biological roles of lncRNA NEAT1 in cardiovascular and cerebrovascular diseases have been disclosed in some experiments, such as the promotion of lncRNA NEAT1 on inflammatory response in myocardial ischemia‐reperfusion injury mice models and the inhibition of lncRNA NEAT1 knockdown on atherosclerosis‐correlated events in vitro . For stroke, previous study displays that lncRNA NEAT1 facilitates oxygen‐glucose deprivation/reoxygenation (OGD/R) injury and neuroinflammation damage of microglial cells, meanwhile, lncRNA NEAT1 enhances intima thickening or vascular occlusion through modulating the phenotype conversion of vascular smooth muscle cells, together with excessive apoptosis of epithelial cells, indicating that lncRNA NEAT1 is a therapeutic target for ischemic stroke . Based on these indications, we hypothesized that lncRNA NEAT1 might play a critical role in AIS development, progression, and prognosis, however, the related evidence was limited.…”

“…14,15 For stroke, previous study displays that lncRNA NEAT1 facilitates oxygen-glucose deprivation/reoxygenation (OGD/R) injury and neuroinflammation damage of microglial cells, meanwhile, lncRNA NEAT1 enhances intima thickening or vascular occlusion through modulating the phenotype conversion of vascular smooth muscle cells, together with excessive apoptosis of epithelial cells, indicating that lncRNA NEAT1 is a therapeutic target for ischemic stroke. 16,17 Based on these indications, we hypothesized that ln-cRNA NEAT1 might play a critical role in AIS development, progression, and prognosis, however, the related evidence was limited.…”