Signal-Dependent Transcriptional Regulation of Vascular Smooth Muscle Cell Differentiation

Vascular smooth muscle cells (VSMCs) play a key role in development as they are the major source of extracellular matrix components of vessel walls. During development, VSMCs will both proliferate and differentiate to form components of the vasculature. Differentiated VSMCs (contractile phenotype) line vessel walls to regulate blood flow. The proliferative phenotype of VSMCs (synthetic phenotype) refers to migration and proliferation of these cells to specific sites to contribute to the formation of the vasculature. Interestingly, VSMCs maintain the ability to proliferate post-natally in response to vascular injury. Therefore, the purpose of this body of work was to investigate the signalling pathways that regulate transcriptional control in VSMCs. Calcium sensitivity in VSMCs is regulated by RhoA/ROCK-mediated inhibition of the myosin light chain phosphatase complex, and alterations in smooth muscle gene expression. We found that calcium signalling stimulates ROCK-mediated phosphorylation of the PP1α inhibitor CPI-17 at threonine 38, leading to derepression of MEF2C by PP1α and increased myocardin expression, which lies upstream of smooth muscle-specific structural genes. Furthermore, TGF-β also potently induces VSMC marker genes at the transcriptional and protein levels in 10T1/2 mouse embryonic fibroblast cells. We found that the potent transcriptional regulator and nuclear retention factor, TAZ, is required for TGF-β induction of smooth muscle genes and is required in the maintenance of the differentiated VSMC phenotype. A synergistic interaction between TAZ and SRF in regulating smooth muscle gene activation and differentiation has also been observed, and TAZ expression enhances SRF binding to the smooth muscle α-actin promoter. This work addresses several important aspects of signalling pathways involved in the regulation of the vascular smooth muscle phenotype and provides a further understanding of the role of SRF in vascular development and vascular disease

The emerging role of epigenetics in therapeutic targeting of cardiomyopathies

Cardiomyopathies (CMPs) are a heterogeneous group of myocardial diseases accountable for the majority of cases of heart failure (HF) and/or sudden cardiac death (SCD) worldwide. With the recent advances in genomics, the original classification of CMPs on the basis of morphological and functional criteria (dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic ventricular cardiomyopathy (AVC)) was further refined into genetic (inherited or familial) and acquired (non-inherited or secondary) forms. Despite substantial progress in the identification of novel CMP-associated genetic variations, as well as improved clinical recognition diagnoses, the functional consequences of these mutations and the exact details of the signaling pathways leading to hypertrophy, dilation, and/or contractile impairment remain elusive. To date, global research has mainly focused on the genetic factors underlying CMP pathogenesis. However, growing evidence shows that alterations in molecular mediators associated with the diagnosis of CMPs are not always correlated with genetic mutations, suggesting that additional mechanisms, such as epigenetics, may play a role in the onset or progression of CMPs. This review summarizes published findings of inherited CMPs with a specific focus on the potential role of epigenetic mechanisms in regulating these cardiac disorders

A novel RhoA/ROCK-CPI-17-MEF2C signaling pathway regulates vascular smooth muscle cell gene expression

Differentiation of vascular smooth muscle cells (VSMC) is a fundamental aspect of normal development and vascular disease. During contraction, VSMCs modulate calcium sensitivity through RhoA/ROCK-mediated inhibition of the myosin light chain phosphatase complex (MLCP). Previous studies have demonstrated that this signaling pathway functions in parallel to increase the expression of smooth muscle genes through the myocardin-family of co-activators. MEF2C fulfills a critical role in VSMC differentiation and regulates myocardin expression, leading us to investigate whether the RhoA/ROCK signaling cascade might regulate MEF2 activity. Depolarization-induced calcium signaling increased the expression of myocardin, which was sensitive to ROCK and p38 MAPK inhibition. We previously identified protein phosphatase 1α (PP1α), a known catalytic subunit of the MLCP in VSMCs, as a potent repressor of MEF2 activity. PP1α inhibition resulted in increased expression of myocardin, while ectopic expression of PP1α inhibited the induction of myocardin by MEF2C. Consistent with these data, shRNA-mediated suppression of a PP1α inhibitor, CPI-17, reduced myocardin expression and inhibited VSMC differentiation, suggesting a pivotal role for CPI-17 in regulating MEF2 activity. These data constitute evidence of a novel signaling cascade that links RhoA-mediated calcium sensitivity to MEF2-dependent myocardin expression in VSMCs through a mechanism involving p38 MAPK, PP1α, and CPI-17

Non-Coding RNAs in Cell-to-Cell Communication: Exploiting Physiological Mechanisms as Therapeutic Targets in Cardiovascular Pathologies

Cardiovascular disease, the leading cause of death worldwide, has been characterized at the molecular level by alterations in gene expression that contribute to the etiology of the disease. Such alterations have been shown to play a critical role in the development of atherosclerosis, cardiac remodeling, and age-related heart failure. Although much is now known about the cellular and molecular mechanisms in this context, the role of epigenetics in the onset of cardiovascular disease remains unclear. Epigenetics, a complex network of mechanisms that regulate gene expression independently of changes to the DNA sequence, has been highly implicated in the loss of homeostasis and the aberrant activation of a myriad of cellular pathways. More specifically, non-coding RNAs have been gaining much attention as epigenetic regulators of various pathologies. In this review, we will provide an overview of the ncRNAs involved in cell-to-cell communication in cardiovascular disease, namely atherosclerosis, cardiac remodeling, and cardiac ageing, and the potential use of epigenetic drugs as novel therapeutic targets

Epigenetics of aging and disease: a brief overview

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Therapeutic Potential of EVs: targeting cardiovascular diseases

Due to their different biological functions, extracellular vesicles (EVs) have great potential from a therapeutic point of view. They are released by all cell types, carrying and delivering different kinds of biologically functional cargo. Under pathological events, cells can increase their secretion of EVs and can release different amounts of cargo, thus making EVs great biomarkers as indicators of pathological progression. Moreover, EVs are also known to be able to transport and deliver cargo to different recipient cells, having an important role in cellular communication. Interestingly, EVs have recently been explored as biological alternatives for the delivery of therapeutics, being considered natural drug delivery carriers. Because cardiovascular disorders (CVDs) are the leading cause of death worldwide, in this review, we will discuss the up-to-date knowledge regarding the biophysical properties and biological components of EVs, focusing on myocardial infarction, diabetic cardiomyopathy, and sepsis-induced cardiomyopathy, three very different types of CVDs