Therapies Targeted at Non-Coding RNAs in Prevention and Limitation of Myocardial Infarction and Subsequent Cardiac Remodeling—Current Experience and Perspectives

Abstract

Myocardial infarction is one of the major causes of mortality worldwide and is a main cause of heart failure. This disease appears as a final point of atherosclerotic plaque progression, destabilization, and rupture. As a consequence of cardiomyocytes death during the infarction, the heart undergoes unfavorable cardiac remodeling, which results in its failure. Therefore, therapies aimed to limit the processes of atherosclerotic plaque progression, cardiac damage during the infarction, and subsequent remodeling are urgently warranted. A hopeful therapeutic option for the future medicine is targeting and regulating non-coding RNA (ncRNA), like microRNA, circular RNA (circRNA), or long non-coding RNA (lncRNA). In this review, the approaches targeted at ncRNAs participating in the aforementioned pathophysiological processes involved in myocardial infarction and their outcomes in preclinical studies have been concisely presented.

ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery

“…The difficulty in obtaining brain tissue from drug resistant epileptic subjects makes it problematic to validate reported data. Michal Kowara et al [1] reviewed miRNAs and lncRNAs associated with atherogenesis as potential targets to improve myocardial infarction prognosis. These authors summarized certain preclinical studies targeting miRNAs as regulators of crucial pathways involved in atherosclerotic plaque progression (miR-33, miR-98, miR-145, and members of the same miRNA cluster miR-494/miR-495), and other miRNAs indirectly associated with atherosclerosis (miR-29, miR-135b, miR-181b, miR-210, miR-335, miR-520c, and let-7g).…”

“…Other strategies tested to assess lncRNA functions include the use of viral vectors, the generation of knockout mice with relevant corresponding natural antisense transcripts using CRISPR/Cas9 gene editing tools [10,11], and the generation of knock-in mice overexpressing lncRNAs. In a current review from this issue, Michal Kowara et al [1] provide some examples of lncRNAs involved in atherosclerosis, such as MALAT1 (using double knock-out animals), lincRNA-p21 (through local injection of an siRNA-expressing lentiviral vector), or RAPIA (down-regulated by a short hairpin delivered through an adenoviral vector), whose activity is in part mediated by miR-183 inhibition. Other lncRNAs identified include those involved in apoptosis, such as KLF-3-AS1 (injection of mesenchymal stem-cell-derived exosomes) or MEG3, those related to the TGF-β pathway, such as a lncRNA called Safe and lnc-Ang362, those related to connective tissue growth factor (CTGF), such as lnc-n379519, and those involved in cardiomyocyte proliferation, such as CRRL (cardiomyocyte regeneration-related lncRNA) and CHRF (cardiac-hypertrophy-related factor).…”

“…Another strategy, reported by Michal Kowara et al in this collection [1], employs a multifunctional biomimetic nanoparticle system, ternary polyplexes coated with ApoA-I resembling HDL particles, which interacts with specific receptors on macrophages and creates a positive feedback loop facilitating drug delivery to the macrophage. Polyplexes employ multi-platforms targeted at different cells such as core-shell NPs, composed of a PGLA core and three external layers, a lipid layer, an ApoA-I layer for enhanced entry into macrophages, and a hyaluronic acid layer for endothelial cell targeting.…”

“…However, barriers to the translation of ncRNA-based therapies to the clinic are related to: (i) the specificity of the targets involved in the main pathways and contributing to disease development or progression, (ii) the local delivery of the molecules at the subcellular level, and (iii) their stability. In this special issue devoted to the potential use of "ncRNA in therapeutics", we have compiled a series of articles about ncRNAs differentially expressed in cardiovascular diseases [1], in bone metabolism-related disorders [2], in epilepsy [3], and in oncology [4], that contribute to disease development or progression and have the potential to be used as biomarkers or targets for therapeutic development. Several clinical trials using various strategies have confirmed the success of ncRNA-based therapies [5].…”

Novel lncRNA-miRNA-mRNA Competing Endogenous RNA Triple Networks Associated Programmed Cell Death in Heart Failure

“…Among these ncRNAs, increasing evidence indicates that lncRNA was widely involved in the pathological process of cardiac development, atherosclerosis, myocardial infarction, hypertension and aneurysm (4)(5)(6). Dysfunction of lncRNAs was also reported in a number of studies of HF (7,8). Specifically, lncRNA MHRT and non-coding NFAT inhibitory factor NRON was found to significantly increase in the plasma of patients with HF (9).…”