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, Available online , doi: 10.26599/1671-5411.2023.06.002
Abstract:
BACKGROUND Abnormal type I collagen (COL1) expression is associated with the development of many cardiovascular diseases. The TGF-beta/Smad signaling pathway and circRNAs have been shown to regulate COL1 gene expression, but the underlying molecular mechanisms are still not fully understood. METHODS Gain- and loss-of-function experiments were prformed to study the effect of circZBTB46 on the expression of alpha 2 chain of type I collagen (COL1A2). Co-immunoprecipitation assay was performed to observe the interaction between two proteins. RNA immunoprecipitation assay and biotin pull-down assay were performed to observe the interaction of circZBTB46 with PDLIM5. RESULTS In this study, we investigated the role of circZBTB46 in regulating COL1A2 expression in human vascular smooth muscle cells (VSMCs). We found that circZBTB46 is expressed in VSMCs and that TGF-beta inhibits circZBTB46 formation by downregulating KLF4 expression through activation of the Smad signaling pathway. CircZBTB46 inhibits the expression of COL1A2 induced by TGF-beta. Mechanistically, circZBTB46 mediates the interaction between Smad2 and PDLIM5, resulting in the inhibition of Smad signaling and the subsequent downregulation of COL1A2 expression. Furthermore, we found that the expression of TGF-beta and COL1A2 is decreased, while circZBTB46 expression is increased in human abdominal aortic aneurysm tissues, indicating that circZBTB46-mediated regulation of TGF-beta/Smad signaling and COL1A2 synthesis in VSMCs plays a crucial role in vascular homeostasis and aneurysm development. CONCLUSIONS CircZBTB46 was identified as a novel inhibitor of COL1 synthesis in VSMCs, highlighting the importance of circZBTB46 and PDLIM5 in regulating TGF-beta/Smad signaling and COL1A2 expression.
, Available online , doi: 10.26599/1671-5411.2023.07.001
Abstract:
OBJECTIVES To investigate the value of CCKBRfl/fl villin-Cre mice as a mouse model of salt-sensitive hypertension (SSH). METHODS In the first part, 2-month-old CCKBRfl/fl villin-Cre mice (CKO) and control CCKBRfl/fl mice (WT) were fed with normal diet (0.4% NaCl) or high salt diet (4% NaCl), separately for 6 weeks. In the rescue study, one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet. The blood pressure, biochemical indexes, and the expression of small intestinal sodium transporters (NHE3, NKCC1, eNaC) was detected. The organ injury markers (MMP2/MMP9) and the histopathological changes of kidneys were observed, whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo. RESULTS The CCKBRfl/fl villin-Cre mice with high salt intake exhibited high blood pressure, increased duodenal sodium absorption and urinary sodium excretion, and with renal injury. The protein expression of NHE3, NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice. Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBRfl/fl villin-Cre mice, but no significant histopathological changes were observed. CONCLUSIONS These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBRfl/fl villin-Cre mice. The CCKBRfl/fl villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.
, Available online , doi: 10.11909/j.issn.1671-5411.2022.10.016
Abstract:
BACKGROUND The molecular mechanisms of heart failure (HF) remain poorly understood. Studies have increasingly found circular RNA (circRNA) exists in heart. The aim of this study is to acquire potential functions of circRNAs in HF. METHODS & RESULTS We integrated RNA sequencing data to identify the characteristics of circRNAs expressed in heart and found that most circRNAs screened were < 2000 nt (89%); moreover, Chromosome 1 and Y contained the largest and least number of circRNAs (10.59% and 0.2%), respectively. Subsequently, a total of 238 differentially expressed circRNAs (DECs) were found and 203 host genes were discovered after excluding duplicate host genes and intergenic circRNAs. However, only 4 of 203 host genes of DECs were checked in differentially expressed genes (DEGs) of HF. Another, Gene Oncology (GO) analysis of DECs host genes was performed to elucidate the underlying pathogenesis of HF, suggesting that binding and catalytic activity accounted for a great part of DECs. The pathways related to immune system, metabolism and signal transduction were significantly enriched. Additionally, 1052 potentially regulated miRNAs from the top 40 DECs were collected to construct a circRNA–miRNA network and found that 470 miRNAs can be regulated by multiple circRNA, while others were regulated by a single circRNA. And further comparison with the top 10 mRNAs and their targeted miRNAs in HF showed DDX3Y and UTY were regulated by the most and least circRNA, respectively. Finally, four selected randomly DECs were validated by qRT-PCR. CONCLUSION These data showed that circRNAs have species and tissue specific expression features; although circRNAs expression independent on host genes, same types of genes between DECs and DEGs worked in HF. CircRNAs could regulate miRNAs as molecular sponges. Our data would enhance understanding of the important roles of circRNAs and lay a foundation for future investigations of HF molecular functions.
, Available online , doi: 10.11909/j.issn.1671-5411.2022.12.011
Abstract:
OBJECTIVES To investigate proarrhythmic substrates of atrial fibrillation (AF) in a canine model of dehydromonophylline (DMCT)-induced pulmonary arterial hypertension (PAH). METHODS All cannines (n = 12) underwent baseline echocardiographic and hemodynamic examinations, 7 of which were injected with DMCT (3.0 mg/kg) to induce PAH via jugular vein cannulation. The control beagles (n = 5) were given the same dose of normal saline. Then, both groups were monitored by insertable cardiac monitors. Hemodynamic, echocardiographic, electrophysiological and histological examinations were performed 8 weeks later. RESULTS In PAH group, two died after the injection (mortality 28.6%). Thus, 10 beagles (PAH group: 5, control group: 5) underwent all the examinations. The pulmonary artery pressure increased significantly while the right atrium (RA) and right ventricle expanded slightly. Spontaneous AF episodes were recorded in all PAH canines 1 week after the injection. The AF burden increased rapidly from 1 week (7.6% ± 1.8%) and remained high after 2-3 weeks (32.0% ± 4.9% at 8 weeks). Compared with the control group, the PAH group had abbreviated effective refractory periods (ERPs), increased atrial ERP dispersion, and slower conduction velocities. Notably, AF susceptibility and atrial remodeling in RA was more significant those in LA, such as increased WOV (39.0 ± 6.5 vs. 28.0 ± 5.7 ms, P = 0.022), enlarged low voltage regions (7.66% ± 0.46% vs. 4.40% ± 0.55%, P < 0.0001) and fibrosis (8.22% ± 0.61% vs. 4.93% ± 0.60%, P < 0.0001). CONCLUSIONS DMCT-induced canine PAH model increased the incidence of spontaneous and induced AF. The electrophysiological and structural remodeling of the RA facilitated the AF genesis.
