Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy

Abstract

Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy. This is especcialy the case for small non-coding microRNAs but was also, although in a smaller scale, convincingly demonstrated for other members of cellular epigenome landscape. Equally important, and clinically most relevant, the reported data indicate that epigenetic marks, particularly certain microRNA signatures, could represent useful non-invasive biomarkers that reflect the disease progression and patients prognosis for recovery after the valve replacement surgery.

Harnessing Mechanosensation in Next Generation Cardiovascular Tissue Engineering

“…Furthermore, transfection of porcine activated VICs with miR-141 resulted in the recovery of physiological signaling of other regulators of valve calcification, bone morphogenic protein-2 (BMP-2) and ALP [ 77 ]. Since VICs respond to mechanical signals of the surrounding ECM, miRNAs interfering with calcific crystal deposition might represent potent therapeutic tools [ 78 ]. Another mechanism by which epigenetics exerts its control is DNA methylation, usually associated with gene expression silencing [ 18 ].…”

“…Another solution to overcome the adverse remodeling of cell-free valve implants could be to directly modulate the activity of genes involved in cell mechanosensation and thus reduce the intracellular transmission of mechanical cues, thereby reducing the transition of cells toward a matrix remodeling and compacting phenotypes. Examples may include the employment of materials with finely tuned viscoelastic properties to maintain a relatively low level of intracellular stress fiber tensioning [ 78 , 79 ] or delivering drugs interfering with downstream effectors of the mechanically-activated signal transduction cascades, e.g., the Hippo-dependent transcriptional pathway [ 101 ] ( Figure 2 ). Interestingly, it has been found that NOTCH signaling reactivation is required for cardiac valve regeneration in the zebrafish model [ 102 ].…”

The Impact of Transcatheter Aortıc Valve Implantatıon on Neutrophıl to Lymphocyte Ratıo: A Retrospective Study

“…Several functional studies have indicated that epigenetic mechanisms play an important role in the initiation and progression of aortic stenosis as well as LVH. These mechanisms could contribute to endothelial dysfunction, disease-prone activation of monocytes and macrophages, and osteogenic transdifferentiation of aortic valve interstitial cells, leading to valvular inflammation, fibrosis, calcification, and pressure overload-induced maladaptive myocardial remodeling and LVH [30]. Villar, et al reported that the regression of hypertrophy at 1-year after release of pressure overload is related to the preoperative myocardial expression of remodeling-related genes.…”

The Genetic Regulation of Aortic Valve Development and Calcific Disease

“…In contrast, LncRNAs are more than 200 nucleotides long and can localize to different sub-cellular depots ( 152 ). While there are limited studies on the epigenetic regulation of cardiogenesis and valvulogenesis ( 153 – 155 ), gene methylation status, and LncRNAs and MiRs profiles have shown to be altered in CAVD and aortic stenosis and these are summarized in Tables 1 , 2 , respectively ( 181 – 183 ).…”