Changes in the structure and function of the left ventricle in patients with gout: A study based on three-dimensional speckle tracking echocardiography.

PURPOSE: Studies have shown that gout can increase the risk of cardiovascular disease. Three-dimensional speckle-tracking echocardiography (3D-STE), a sensitive imaging technology, enables the detection of subtle myocardial dysfunctions. Our aim is to evaluate the left ventricular (LV) functions in patients with gout using 3D-STE. METHODS: 80 subjects: 40 with gout and 40 as normal controls were involved. We obtained and analyzed these parameters from the dynamic images of a 3D full-volume dataset: global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), Twist, 16-segmental time-to-peak longitudinal strain (TTP) and systolic dyssynchrony index (SDI)besides other relevant parameters. RESULTS: Compared with the normal group, gout patients were more likely to have left ventricular remodeling. The patients with gout showed decreased Em, increased E/Em and larger volume index of the left atrium (LAVI) indicating reduced diastolic function. The peak GLS (-17.42 ± 2.02 vs. -22.40 ± 2.57, P < 0.001), GCS (-27.04 ± 3.75 vs. -34.85 ± 4.99, P < 0.001), GRS (38.22 ± 4.28 vs. 46.15 ± 5.17, P < 0.001), and Twist (15.18 ± 5.45 vs. 19.02 ± 5.29, P = 0.015) were significantly lower in patients with gout than in healthy participants. The SDI (5.57 ± 1.46 vs. 4.91 ± 1.19, P = 0.016) was significantly increased in patients with gout compared with normal controls. There was no significant between-group difference in TTP (P = 0.43). The systolic GLS, GRS and GCS peak values increased gradually from the base to the apex, with the lowest values in the basal segment in patients with gout. Receiver-operating characteristic curve analysis revealed among these strains GLS has the largest area under the curve (AUC: 0.93, P < 0.001), the cutoff value of -18.97% with a sensitivity and specificity of 80.0% and 92.0%, respectively, for differentiating two groups. A multivariate linear regression analysis shows that the relationship between gout and strain parameters including GLS, GRS, and GCS is statistically significant (P < 0.001). CONCLUSION: Although patients with gout having a normal ejection fraction, structural remodeling of the left ventricle and subclinical LV deformation may occur. 3D-STE can detect subtle cardiac dysfunctions in patients with gout at an early stage.

The regulatory roles of aminoacyl-tRNA synthetase in cardiovascular disease.

Aminoacyl-tRNA synthetases (ARSs) are widely found in organisms, which can activate amino acids and make them bind to tRNA through ester bond to form the corresponding aminoyl-tRNA. The classic function of ARS is to provide raw materials for protein biosynthesis. Recently, emerging evidence demonstrates that ARSs play critical roles in controlling inflammation, immune responses, and tumorigenesis as well as other important physiological and pathological processes. With the recent development of genome and exon sequencing technology, as well as the discovery of new clinical cases, ARSs have been reported to be closely associated with a variety of cardiovascular diseases (CVDs), particularly angiogenesis and cardiomyopathy. Intriguingly, aminoacylation was newly identified and reported to modify substrate proteins, thereby regulating protein activity and functions. Sensing the availability of intracellular amino acids is closely related to the regulation of a variety of cell physiology. In this review, we summarize the research progress on the mechanism of CVDs caused by abnormal ARS function and introduce the clinical phenotypes and characteristics of CVDs related to ARS dysfunction. We also highlight the potential roles of aminoacylation in CVDs. Finally, we discuss some of the limitations and challenges of present research. The current findings suggest the significant roles of ARSs involved in the progress of CVDs, which present the potential clinical values as novel diagnostic and therapeutic targets in CVD treatment.

5'-tiRNA-Cys-GCA regulates VSMC proliferation and phenotypic transition by targeting STAT4 in aortic dissection.

Accumulating evidence shows that tRNA-derived fragments are a novel class of functional small non-coding RNA; however, their roles in aortic dissection (AD) are still unknown. In this study, we found that 5'-tiRNA-Cys-GCA was significantly downregulated in human and mouse models of aortic dissection. The abnormal proliferation, migration, and phenotypic transition of vascular smooth muscle cells (VSMCs) played a crucial role in the initiation and progression of aortic dissection, with 5'-tiRNA-Cys-GCA as a potential phenotypic switching regulator, because its overexpression inhibited the proliferation and migration of VSMCs and increased the expression of contractile markers. In addition, we verified that signal transducer and activator of transcription 4 (STAT4) was a direct downstream target of 5'-tiRNA-Cys-GCA. We found that the STAT4 upregulation in oxidized low-density lipoprotein (ox-LDL)-treated VSMCs, which promoted cell proliferation, migration, and phenotypic transformation, was reversed by 5'-tiRNA-Cys-GCA. Furthermore, 5'-tiRNA-Cys-GCA treatment reduced the incidence and prevented the malignant process of angiotensin II- and ß-aminopropionitrile-induced AD in mice. In conclusion, our findings reveal that 5'-tiRNA-Cys-GCA is a potential regulator of the AD pathological process via the STAT4 signaling pathway, providing a novel clinical target for the development of future treatment strategies for aortic dissection.

Identification of transfer RNA-derived fragments and their potential roles in aortic dissection.

Emerging evidence suggests that majority of the transfer RNA (tRNA)-derived small RNA, including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), play a significant role in the molecular mechanisms underlying some human diseases. However, expression of tRFs/tiRNAs and their potential roles in aortic dissection (AD) remain unclear. This study examined the expression characteristics and explored the functional roles of tRFs/tiRNAs in AD using RNA-sequencing, bioinformatics, real-time quantitative reverse transcription polymerase chain reaction, and loss- and gain-of-function analysis. Results revealed that a total of 41 tRFs/tiRNAs were dysregulated in the AD group compared to the control group. Among them, 12 were upregulated and 29 were downregulated (fold change≥1.5 and p < 0.05). RT-qPCR results revealed that expressions of tRF-1:30-chrM.Met-CAT was significantly upregulated, while that of tRF-54:71-chrM.Trp-TCA and tRF-1:32-chrM.Cys-GCA were notably downregulated; expression patterns were consistent with the RNA sequencing data. Bioinformatic analysis showed that a variety of related pathways might be involved in the pathogenesis of AD. Functionally, tRF-1:30-chrM.Met-CAT could facilitate proliferation, migration, and phenotype switching in vascular smooth muscle cells (VSMCs), which might serve as a significant regulator in the progression of AD. In summary, the study illustrated that tRFs/tiRNAs expressed in AD tissues have potential biological functions and may act as promising biomarkers or therapeutic targets for AD.

Expression profiles and potential roles of transfer RNA-derived small RNAs in atherosclerosis.

Knowledge regarding the relationship between the molecular mechanisms underlying atherosclerosis (AS) and transfer RNA-derived small RNAs (tsRNAs) is limited. This study illustrated the expression profile of tsRNAs, thus exploring its roles in AS pathogenesis. Small RNA sequencing was performed with four atherosclerotic arterial and four healthy subject samples. Using bioinformatics, the protein-protein interaction network and cellular experiments were constructed to predict the enriched signalling pathways and regulatory roles of tsRNAs in AS. Of the total 315 tsRNAs identified to be dysregulated in the AS group, 131 and 184 were up-regulated and down-regulated, respectively. Interestingly, the pathway of the differentiated expression of tsRNAs in cell adhesion molecules (CAMs) was implicated to be closely associated with AS. Particularly, tRF-Gly-GCC might participate in AS pathogenesis via regulating cell adhesion, proliferation, migration and phenotypic transformation in HUVECs and VSMCs. In conclusion, tsRNAs might help understand the molecular mechanisms of AS better. tRF-Gly-GCC may be a promising target for suppressing abnormal vessels functions, suggesting a novel strategy for preventing the progression of atherosclerosis.

The cellular function and molecular mechanism of formaldehyde in cardiovascular disease and heart development.

As a common air pollutant, formaldehyde is widely present in nature, industrial production and consumer products. Endogenous formaldehyde is mainly produced through the oxidative deamination of methylamine catalysed by semicarbazide-sensitive amine oxidase (SSAO) and is ubiquitous in human body fluids, tissues and cells. Vascular endothelial cells and smooth muscle cells are rich in this formaldehyde-producing enzyme and are easily damaged owing to consequent cytotoxicity. Consistent with this, increasing evidence suggests that the cardiovascular system and stages of heart development are also susceptible to the harmful effects of formaldehyde. Exposure to formaldehyde from different sources can induce heart disease such as arrhythmia, myocardial infarction (MI), heart failure (HF) and atherosclerosis (AS). In particular, long-term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations than long-term exposure to low concentrations of formaldehyde. Specifically, the ability of mouse embryos to effect formaldehyde clearance is far lower than that of the rat embryos, more readily allowing its accumulation. Formaldehyde may also exert toxic effects on heart development by inducing oxidative stress and cardiomyocyte apoptosis. This review focuses on the current progress in understanding the influence and underlying mechanisms of formaldehyde on cardiovascular disease and heart development.

Nicotine: Regulatory roles and mechanisms in atherosclerosis progression.

Smoking is an independent risk factor for atherosclerosis. The smoke produced by tobacco burning contains more than 7000 chemicals, among which nicotine is closely related to the occurrence and development of atherosclerosis. Nicotine, a selective cholinergic agonist, accelerates the formation of atherosclerosis by stimulating nicotinic acetylcholine receptors (nAChRs) located in neuronal and non-neuronal tissues. This review introduces the pathogenesis of atherosclerosis and the mechanisms involving nicotine and its receptors. Herein, we focus on the various roles of nicotine in atherosclerosis, such as upregulation of growth factors, inflammation, and the dysfunction of endothelial cells, vascular smooth muscle cells (VSMC) as well as macrophages. In addition, nicotine can stimulate the generation of reactive oxygen species, cause abnormal lipid metabolism, and activate immune cells leading to the onset and progression of atherosclerosis. Exosomes, are currently a research hotspot, due to their important connections with macrophages and the VSMC, and may represent a novel application into future preventive treatment to promote the prevention of smoking-related atherosclerosis. In this review, we will elaborate on the regulatory mechanism of nicotine on atherosclerosis, as well as the effects of interference with nicotine receptors and the use of exosomes to prevent atherosclerosis development.

tsRNAs: Novel small molecules from cell function and regulatory mechanism to therapeutic targets.

tsRNAs are small fragments of RNAs with specific lengths that are generated by particular ribonucleases, such as dicer and angiogenin (ANG), clipping on the rings of transfer RNAs (tRNAs) in specific cells and tissues under specific conditions. Depending on where the splicing site is, tsRNAs can be segmented into two main types, tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs). Many studies have shown that tsRNAs are functional molecules, not the random degradative products of tRNAs. Notably, due to their regulatory mechanism in regulating mRNA stability, transcription, ribosomal RNA (rRNA) synthesis and RNA reverse transcription, tsRNAs are significantly involved in the cell function, such as cell proliferation, migration, cycle and apoptosis, as well as the occurrence and development of a variety of diseases. In addition, tsRNAs may represent a new generation of clinical biomarkers or therapeutic targets because of their stable structures, high conservation and widely distribution, particularly in the peripheral tissues, bodily fluids and exosomes. In this review, we describe the generation, function and mechanism of tsRNAs and illustrate the current research progress of tsRNAs in various diseases, highlight their potentials as biomarkers and therapeutic targets in clinical application. Although our understanding of tsRNAs is still in infancy, the application prospects shown in this field deserve further exploration.

ßII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases.

ßII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, ßII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of ßII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, ßII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered ßII spectrin expression in tumors indicated that ßII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of ßII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of ßII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of ßII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of ßII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of ßII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.

miR-153-3p Targets ßII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis.

Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to the fetus through placental circulation, causing miscarriage and congenital heart disease (CHD). Studies have shown that ßII spectrin is necessary for cardiomyocyte survival and differentiation, and its loss leads to heart development defects and cardiomyocyte apoptosis. Additionally, previous studies have demonstrated that miRNA is essential in heart development and remodeling. However, whether miRNA regulates FA-induced CHD and cardiomyocyte apoptosis remains unclear. Methods: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Real-time quantitative PCR (RT-qPCR) and Western blot were performed to examine the level of miR-153-3p, ßII spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression in embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Apoptotic cell populations were evaluated by flow cytometry and Tunel. Luciferase activity assay and RNA pull-down assay were used to detect the interaction between miR-153-3p and ßII spectrin. Masson's trichrome staining detects the degree of tissue fibrosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry were used to detect the expression of miR-153-3p and ßII spectrin in tissues. Results: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis, our studies indicate that miR-153-3p plays a regulatory role by directly targeting ßII spectrin to promote cardiomyocyte apoptosis. miR-153-3p mainly regulates cardiomyocyte apoptosis by regulating the expression of caspase7, further elucidating the importance of apoptosis in heart development. Finally, the results with our animal model revealed that targeting the miR-153-3p/ßII spectrin pathway effectively regulated FA-induced damage during heart development. Recovery experiments with miR-153-3p antagomir resulted in the reversal of FA-induced cardiomyocyte apoptosis and fetal cardiac fibrosis. Conclusion: This study investigated the molecular mechanism underpinning the role of ßII spectrin in FA-induced CHD and the associated upstream miRNA pathway. The study findings suggest that miR-153-3p may provide a potential target for the clinical diagnosis and treatment of CHD.

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. Increasing reports demonstrated that non-coding RNAs (ncRNAs) have been crucially involved in the development of CVDs. Piwi-interacting RNAs (piRNAs) are a novel cluster of small non-coding RNAs with strong uracil bias at the 5' end and 2'-O-methylation at the 3' end that are mainly present in the mammalian reproductive system and stem cells and serve as potential modulators of developmental and pathophysiological processes. Recently, piRNAs have been reported to be widely expressed in human tissues and can potentially regulate various diseases. Specifically, concomitant with the development of next-generation sequencing techniques, piRNAs have been found to be differentially expressed in CVDs, indicating their potential involvement in the occurrence and progression of heart diseases. However, the molecular mechanisms and signaling pathways involved with piRNA function have not been fully elucidated. In this review, we present the current understanding of the piRNAs from the perspectives of biogenesis, characteristics, biological function, and regulatory mechanisms, and highlight their potential roles and underlying mechanisms in CVDs, which will provide new insights into the potential applications of piRNAs in the clinical diagnosis, prognosis, and therapeutic strategies for heart diseases.

Non-coding RNAs in aortic dissection: From biomarkers to therapeutic targets.

Aortic dissection (AD) is the rupture of the aortic intima, causing the blood in the cavity to enter the middle of the arterial wall. Without urgent and proper treatment, the mortality rate increases to 50% within 48 hours. Most patients present with acute onset of symptoms, including sudden severe pain and complex and variable clinical manifestations, which can be easily misdiagnosed. Despite this, the molecular mechanisms underlying AD are still unknown. Recently, non-coding RNAs have emerged as novel regulators of gene expression. Previous studies have proven that ncRNAs can regulate several cardiovascular diseases; therefore, their potential as clinical biomarkers and novel therapeutic targets for AD has aroused widespread interest. To date, several studies have reported that microRNAs are crucially involved in AD progression. Additionally, several long non-coding RNAs and circular RNAs have been found to be differentially expressed in AD samples, suggesting their potential roles in vascular physiology and disease. In this review, we discuss the functions of ncRNAs in AD pathophysiology and highlight their potential as biomarkers and therapeutic targets for AD. Meanwhile, we present the animal models previously used for AD research, as well as the specific methods for constructing mouse or rat AD models.