Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo. Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it may be a promising therapeutic target for the treatment of proliferative vascular diseases.

Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis.

Background Coronary heart disease incidence, mortality and short-term case-fatality have improved substantially during the past decades. Recent changes in the long-term prognosis among survivors of acute coronary syndrome are less well known. Our aim was to investigate the long-term prognosis of acute coronary syndrome. Design An observational myocardial infarction register study. Methods Data was derived from the population based Finnish Myocardial Infarction register. Patients aged 35 or higher, who had their first acute coronary syndrome during 1993–2011 and survived the first 28 days, were included in the analysis (n = 13,336). Endpoints were fatal and non-fatal cardiovascular disease events and all-cause mortality at one year and three years after the index event. We also compared the prognosis of acute coronary syndrome survivors with the prognosis of an apparently healthy population with the same age, sex and area of residence, derived from the FINRISK study. Results Significant declines over time were observed in the risk of a new cardiovascular disease event. At three year follow-up the age- and study area-adjusted hazard ratio per calendar year was 0.969 (95% confidence interval 0.960–0.977, p = 4.63 × 10−13) among men and 0.969 (95% confidence interval 0.961–0.978, p = 1.01 × 10−11) among women. Despite the improvement in prognosis, the age-standardized three year cardiovascular disease free survival of acute coronary syndrome patients was significantly lower than in the FINRISK control group (for men p = 6.64 × 10−27 and for women p = 2.11 × 10−15). Conclusion The prognosis of acute coronary syndrome survivors has improved during the 18-year period but is still much worse than the prognosis of comparable general population.

Trends in long-term prognosis after acute coronary syndrome

The mechanisms that underlie the pathophysiology of aging, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and stroke are not fully understood and have been the focus of intense and constant investigation worldwide. Studies that provide insights on aging and age-related disease mechanisms are critical for advancing novel therapies that promote successful aging and prevent or cure multiple age-related diseases. The April 2019 issue of the journal, "Aging & Disease" published a series of articles that confer fresh insights on numerous age-related conditions and diseases. The age-related topics include the detrimental effect of overweight on energy metabolism and muscle integrity, senoinflammation as the cause of neuroinflammation, the link between systemic C-reactive protein and brain white matter loss, the role of miR-34a in promoting healthy heart and brain, the potential of sirtuin 3 for reducing cardiac and pulmonary fibrosis, and the promise of statin therapy for ameliorating asymptomatic intracranial atherosclerotic stenosis. Additional aging-related articles highlighted the involvement of miR-181b-5p and high mobility group box-1 in hypertension, Yes-associated protein in cataract formation, multiple miRs and long noncoding RNAs in coronary artery disease development, the role of higher meat consumption on sleep problems, and the link between glycated hemoglobin and depression. The topics related to ALS suggested that individuals with higher education and living in a rural environment have a higher risk for developing ALS, and collagen XIX alpha 1 is a prognostic biomarker of ALS. The topics discussed on AD implied that extracellular amyloid β42 is likely the cause of intraneuronal neurofibrillary tangle accumulation in familial AD and traditional oriental concoctions may be useful for slowing down the progression of AD. The article on stroke suggested that inhibition of the complement system is likely helpful in promoting brain repair after ischemic stroke. The significance of the above findings for understanding the pathogenesis in aging, ALS, AD, and stroke, slowing down the progression of aging, ALS and AD, and promoting brain repair after stroke are discussed.

Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease

The distinct organization of the brain's vasculature ensures the adequate delivery of oxygen and nutrients during development and adulthood. Acute and chronic pathological changes of the vascular s ...

https://www.zora.uzh.ch/id/eprint/194701/1/Rust_et_al_Frontiers_2020.pdf

A Practical Guide to the Automated Analysis of Vascular Growth, Maturation and Injury in the Brain

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 β-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.

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

Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. High mobility group box-1 (HMGB1) has been reported to be involved in several pathogenic processes including VSMC proliferation and migration. The present study was designed to determine the role of HMGB1 in VSMC phenotypic transformation in hypertension. First, we demonstrated that HMGB1 was elevated in a model of Ang II-induced VSMC phenotypic transformation, which showed down-regulation of contractile proteins and up-regulation of synthetic proteins. Knockdown of HMGB1 and losartan could block the phenotypic transformation. Next, we identified three potential miRNAs for upstream regulation of HMGB1 by bioinformatic analysis; only miR-181b-5p was significantly down-regulated in Ang II-treated cells. Co-treating the cells with miR-181b-5p mimics suppressed HMGB1 expression as well as the phenotypic transformation, migration, and proliferation. Furthermore, the luciferase reporter gene assay confirmed the direct interaction between miR-181b-5p and HMGB1. Finally, to extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers. Based on these observations, we conclude that the down-regulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. Our findings also highlight that the plasma levels of miR-181b-5p and HMGB1 may serve as novel biomarkers for vascular remodeling in the hypertensive patients.

Involvement of the MiR-181b-5p/HMGB1 Pathway in Ang II-induced Phenotypic Transformation of Smooth Muscle Cells in Hypertension.

Background Previous studies have shown that beta 2-microglobulin (B2M) could predict all-cause mortality and cardiovascular mortality in various groups of people. However, the relationship between B2M and severity of coronary stenosis in patients with acute coronary syndrome has not been established. Methods We enrolled 872 consecutive patients admitted with acute coronary syndrome in our study. All participants underwent coronary angiography examination or stent implantation after admission. The severity of coronary stenosis was assessed by Gensini score and the presentation of triple-vessel disease. B2M and other biochemical parameters were measured. All subjects were divided into quartiles of B2M. Multivariate linear regression and logistic regression were applied in the analysis. Results Gensini score and the prevalence of triple-vessel disease were elevated in accordance with increasing B2M quartiles (p=0.002 and 0 0.05 for both). Conclusion Our data indicated that B2M was an independent risk factor of coronary stenosis in patients with acute coronary syndrome.

Beta 2-Microglobulin and the Severity of Coronary Stenosis in Patients With Acute Coronary Syndrome.

ABSTRACT Ovarian cancer (OC) has the highest mortality rate among gynecological cancers, which progresses owing to dysregulated microRNAs (miRNAs) expression. Our study attempts to reveal the mechanism by which decreased miR-324-3p expression suppresses OC proliferation. Quantitative real-time PCR, western blotting, in situ hybridization, and immunohistochemistry were performed to estimate miR-324-3p and WNK2 expression levels in OC cells and tissues. Cell Counting Kit-8, colony formation, EdU, and transwell assays were performed to analyze the influence of miR-324-3p and WNK2 on the proliferation and invasion ability of OC cells. Subsequently, xenograft models were established to examine the effects of WNK2 on OC cell proliferation in vivo, and databases and luciferase reporter assays were used to test the relationship between miR-324-3p and WNK2 expression. Then, we showed that miR-324-3p expression is decreased in OC cells and tissues, indicating its inhibitory effect on OC cell proliferation. Quantitative real-time PCR and luciferase reporter assays demonstrated that miR-324-3p inhibited WNK2 expression by directly binding to its 3’ untranslated region. WNK2, an upregulated kinase, promotes the proliferation and invasion of OC cells by activating the RAS pathway. Moreover, WNK2 can partly reverse the inhibitory effects of miR-324-3p on OC cell proliferation. Hence, we demonstrate that miR-324-3p suppressed ovarian cancer progression by targeting the WNK2/RAS pathway. Our study provides theoretical evidence for the clinical application potential of miR-324-3p. Graphical Abstract

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2056314?needAccess=true

Fengjuan Li

Papers

Involvement of the MiR-181b-5p/HMGB1 Pathway in Ang II-induced Phenotypic Transformation of Smooth Muscle Cells in Hypertension.

Beta 2-Microglobulin and the Severity of Coronary Stenosis in Patients With Acute Coronary Syndrome.

microRNA-324-3p suppresses the aggressive ovarian cancer by targeting WNK2/RAS pathway