Circular RNA (circRNA), a novel type of endogenous noncoding RNA (ncRNA), has become a research hotspot in recent years. CircRNAs are abundant and stably exist in creatures, and they are found with covalently closed loop structures in which they are quite different from linear RNAs. Nowadays, an increasing number of scientists have demonstrated that circRNAs may have played an essential role in the regulation of gene expression, especially acting as miRNA sponges, and have described the potential mechanisms of several circRNAs in diseases, hinting at their clinical therapeutic values. In this review, the authors summarized the current understandings of the biogenesis and properties of circRNAs and their functions and role as biomarkers in cardiovascular diseases.

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Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory response in macrophages via the transcription factor NF-κB. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not completely appreciated. Herein we describe a role for myocardin related transcription factor A, or MRTF-A, in this process. MRTF-A over-expression potentiated while MRTF-A silencing dampened NF-κB dependent pro-inflammatory transcription. MRTF-A deficiency also alleviated the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in a NF-κB dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-κB. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-κB target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5, and SET1, down-regulated the production of pro-inflammatory mediators and impaired the NF-κB kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies.

Rationale: Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus–induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive. Objective: This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms. Methods and Results: IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of α-SMA (α-smooth muscle actin) and collagen I/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6C low and major histocompatibility complex II low /C-C motif chemokine receptor type 2 − (MHC II low CCR2 − ) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) β1 in macrophages by inducing GP130 signaling, via IL12Rβ2 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6C low macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35–treated MI mice showed increased expression of α-SMA and collagen within scars, correlating with decreased left ventricular rupture rates. Conclusions: IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1 + Ly6C low macrophage survival.

Rationale Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the up-regulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined. Objective Our goal was to determine the involvement of Brg1 and Brm in CAM transactivation and its relevance in the pathogenesis of atherosclerosis. Methods and Results In the present study, we report that pro-inflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Over-expression of Brg1 and Brm promoted whereas knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by NF-κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe−/− mice on a Western diet. Conclusion Therefore, our data suggest that Brg1 and Brm integrate various pro-inflammatory cues into CAM transactivation and endothelial malfunction and as such may serve as potential therapeutic targets in treating inflammation related cardiovascular diseases.

-Excessive accumulation of reactive oxygen species (ROS), catalyzed by the NADPH oxidases (NOX), is involved in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying epigenetic mechanism remains elusive. -We evaluated the potential role of megakaryocytic leukemia 1, or MKL1, as a bridge linking epigenetic activation of NOX to ROS production and cardiac ischemia-reperfusion injury. -Following I/R injury, MKL1 deficient (KO) mice exhibited smaller myocardial infarction along with improved heart function compared to wild type (WT) littermates. Similarly, pharmaceutical inhibition of MKL1 with CCG-1423 also attenuated myocardial infarction and improved heart function in mice. Amelioration of I/R injury as a result of MKL1 deletion or inhibition was accompanied by reduced ROS and In response to I/R, MKL1 levels were specifically elevated in macrophages, but not in cardiomyocytes, in the heart. Of note, macrophage-specific deletion (MφcKO), instead of cardiomyocyte-restricted ablation (CMcKO), of MKL1 in mice led to similar improvements of infarct size, heart function, and myocardial ROS generation. Reporter assay and ChIP assay revealed that MKL1 directly bound to the promoters of NADPH oxidase (NOX) genes to activate NOX transcription. Mechanistically, MKL1 recruited the histone acetyltransferase MOF to modify the chromatin structure surrounding the NOX promoters. Knockdown of MOF in macrophages blocked hyoxia/re-oxygenation-induced NOX transactivation and ROS accumulation. Of importance, pharmaceutical inhibition of MOF with MG-149 significantly down-regulated NOX1/NOX4 expression, dampened ROS production, and normalized myocardial function in mice exposed to I/R injury. Finally, administration of a specific NOX1/4 inhibitor GKT137831 dampened ROS generation and rescued heart function following I/R in mice. -Our data delineate an MKL1-MOF-NOX axis in macrophages that contributes to I/R injury and as such have provided novel therapeutic targets in the treatment of ischemic heart disease.

Heart failure (HF) is the single largest cause for increased hospitalization after fine particulate matter (PM2.5) exposure. Patients with left HF often progress to right ventricular (RV) failure even with optimal medical care. An increase of PM2.5 of 10 μg per cubic meter was associated with a 76% increase in the risk of death from cardiovascular disease in 4 years' period. However, the role and mechanism of PM2.5 in HF progression are not known. Here we investigated the role of PM2.5 exposure in mice with existing HF mice produced by transverse aortic constriction (TAC). TAC-induced HF caused lung inflammation, vascular remodeling and RV hypertrophy. We found increased PM2.5 profoundly exacerbated lung oxidative stress in mice with existing left HF. To our surprise, PM2.5 exposure had no effect on LV hypertrophy and function, but profoundly exacerbated lung inflammation, vascular remodeling, and RV hypertrophy in mice with existing left HF. These striking findings demonstrate that PM2.5 and/or air pollution is a critical factor for overall HF progression by regulating lung oxidative stress, inflammation and remodeling as well as RV hypertrophy. Improving air quality may save HF patients from a dismal fate.

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