MicroRNAs in Valvular Heart Diseases: Biological Regulators, Prognostic Markers and Therapeutical Targets

Abstract

miRNAs have recently attracted investigators’ interest as regulators of valvular diseases pathogenesis, diagnostic biomarkers, and therapeutical targets. Evidence from in-vivo and in-vitro studies demonstrated stimulatory or inhibitory roles in mitral valve prolapse development, aortic leaflet fusion, and calcification pathways, specifically osteoblastic differentiation and transcription factors modulation. Tissue expression assessment and comparison between physiological and pathological phenotypes of different disease entities, including mitral valve prolapse and mitral chordae tendineae rupture, emerged as the best strategies to address miRNAs over or under-representation and thus, their impact on pathogeneses. In this review, we discuss the fundamental intra- and intercellular signals regulated by miRNAs leading to defects in mitral and aortic valves, congenital heart diseases, and the possible therapeutic strategies targeting them. These miRNAs inhibitors are comprised of antisense oligonucleotides and sponge vectors. The miRNA mimics, miRNA expression vectors, and small molecules are instead possible practical strategies to increase specific miRNA activity. Advantages and technical limitations of these new drugs, including instability and complex pharmacokinetics, are also presented. Novel delivery strategies, such as nanoparticles and liposomes, are described to improve knowledge on future personalized treatment directions.

miRNAs in Cardiac Myxoma: New Pathologic Findings for Potential Therapeutic Opportunities

“…MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, contributing to all major cellular processes. miRNAs have been recently recognized as biomarkers and possible therapeutic targets for the diagnosis and treatment of diseases [ 1 ]. A single miRNA can target many genes, affecting various gene expressions [ 2 ].…”

“…The importance of miRNAs in cardiac development and heart function in cases of ischemic disease has been shown in recent years [ 1 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Early stages of cardiac development are controlled by miR-1 and miR-133a, resulting in commitment of cardiac-specific muscle lineage from embryonic stem cells and mesodermal precursors [ 12 ].…”

“…Cardiac automaticity is regulated by miR-1/133a, while miR-208/499 regulates expression of contractile proteins. In cardiac pathology, expression of cardiac miRNAs is markedly altered [ 1 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], leading to acute (ischemia-reperfusion and apoptosis) and chronic (fibrosis, hypertrophy, and remodeling) adverse effects. In acute myocardial infarction, circulating levels of cardiac miRNAs are significantly elevated, making them a promising marker for early diagnosis [ 5 ].…”

Flow-Responsive Noncoding RNAs in the Vascular System: Basic Mechanisms for the Clinician

“…LncRNA are able to exert an array of biological func tions, including: (1) regulation of DNA transcription by acting with a transcription facto (2) epigenetic silencing and repressing the histone modification via chromatin interaction (3) mRNA translation (4) post-translational regulation through miRNA sponges o circRNA, (5) scaffold of protein complex, (6) shorter ncRNAs (siRNA) generation (Figur 1B). Noncoding RNAs are largely involved in cardiovascular physiology, atherosclerosi [35], and multiple cardiovascular diseases [36], as chronic and acute coronary syndrome [6,[37][38][39][40][41], vascular remodeling [29,42], valvular heart disease [43][44][45][46][47], generation and pro gression of ectopic calcifications in the cardiovascular system [48][49][50][51][52][53][54], platelet functio [55][56][57][58][59], heart failure and stroke [60][61][62][63][64][65][66][67][68][69][70]. Evidence of the impact of flow conditions on cir culating ncRNA derives both from observations on pathological changes, such as cardia valve disease, vascular stenoses or aneurysm, but also from physiological conditions, suc as exercise [68].…”

“…This review focuses on regulatory noncoding RNAs that are directly or indirectl responsive to flow and their involvement with cardiovascular effects of altered bloo flow, with a focus on the potential clinical relevance and the underlying molecular mech anisms and their possible use as clinical biomarkers [71]. As relevant evidence is no equally available for all ncRNAs sub-categories, some specific ncRNAs, including siR NAs, snoRNA or piRNA are not mentioned in this review due to lack of evidence in rela Noncoding RNAs are largely involved in cardiovascular physiology, atherosclerosis [35], and multiple cardiovascular diseases [36], as chronic and acute coronary syndromes [6,[37][38][39][40][41], vascular remodeling [29,42], valvular heart disease [43][44][45][46][47], generation and progression of ectopic calcifications in the cardiovascular system [48][49][50][51][52][53][54], platelet function [55][56][57][58][59], heart failure and stroke [60][61][62][63][64][65][66][67][68][69][70]. Evidence of the impact of flow conditions on circulating ncRNA derives both from observations on pathological changes, such as cardiac valve disease, vascular stenoses or aneurysm, but also from physiological conditions, such as exercise…”