Associations between dietary diversity and dyslipidemia among Japanese workers: cross-sectional study and longitudinal study findings.

OBJECTIVE: The aim of this study was to determine the associations between dietary diversity and risk of dyslipidemia in Japanese workers. METHODS: The cross-sectional study included 1399 participants aged 20-63 years and the longitudinal study included 751 participants aged 20-60 years in 2012-2013 (baseline) who participated at least once from 2013 to 2017 with cumulative participation times of 4.9 times. Dietary intake was assessed using a food frequency questionnaire, and dietary diversity score (DDS) was determined using the Quantitative Index for Dietary Diversity. Dyslipidemia was diagnosed when at least one of the following conditions was met: hypertriglyceridemia, high LDL-cholesterol, low HDL-cholesterol, high non-HDL-cholesterol, and a history of dyslipidemia. Multivariable logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for dyslipidemia with control of confounding factors in cross-sectional analysis. Generalized estimating equations were used for calculating the ORs (95% CI) for dyslipidemia in the follow-up period according to the DDS at baseline with control of confounding factors in longitudinal analysis. RESULTS: Cross-sectional analysis showed that the highest DDS reduced the odds of dyslipidemia in men (OR [95% CI] in Tertile 3: 0.67 [0.48-0.95], p value = 0.023). In longitudinal analysis, a moderate DDS reduced the risk of dyslipidemia (OR [95% CI] in Tertile 2: 0.21 [0.07-0.60], p value = 0.003) in women. CONCLUSIONS: The results of cross-sectional analysis in this study suggest that the higher diversity of diet might reduce the presence of dyslipidemia in men and the results of longitudinal analysis suggest that a moderate DDS might reduce the risk of dyslipidemia in women. Further studies are needed since the results of cross-sectional and longitudinal analyses in this study were inconsistent.

Associations between dietary diversity and high sensitive C-reactive protein among Japanese workers: findings of a cross-sectional and longitudinal study.

PURPOSE: To clarify the association between dietary diversity and inflammatory status in Japanese workers. METHODS: Of 1,460 men and women aged 20-64 years in 2010 (baseline), those who were followed-up at least once between 2011 and 2018 were included in this study; 1,433 participants and 745 participants were included in the cross-sectional and longitudinal analyses, respectively. Dietary intake was assessed using a food frequency questionnaire at baseline, and the dietary diversity score was determined using the Quantitative Index for Dietary Diversity (QUANTIDD). High-sensitivity C-reactive protein (hs-CRP) was taken to indicate inflammatory status at the baseline and follow-up surveys. In the cross-sectional analysis using baseline data, a generalized linear model was used to calculate adjusted means and 95% confidence intervals (CIs) for hs-CRP according to the QUANTIDD score. In the longitudinal analysis, generalized estimating equations were used to calculate the adjusted mean (95% CI) for hs-CRP in follow-up according to the QUANTIDD score at baseline. RESULTS: In the cross-sectional analysis, the hs-CRP concentration in male participants was significantly lower in those who had a high QUANTIDD score (adjusted mean [95% CI]: 0.074 [0.009-0.140] mg/dL in the lower group vs. 0.038 [-0.029-0.105] mg/dL in the higher group, p-value = 0.034). In the longitudinal analysis, the hs-CRP concentration of male participants also tended to be lower in those with higher QUANTIDD scores (p-value = 0.103). In both the cross-sectional and longitudinal analyses in women, there was no significant difference between the lower and higher QUANTIDD score groups. CONCLUSION: These findings suggest that, in male Japanese workers, higher dietary diversity might be important for maintaining a low inflammatory status.

Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.

Deregulation of Drosha in the pathogenesis of hereditary hemorrhagic telangiectasia.

PURPOSE OF REVIEW: The TGFß (transforming growth factor ß) superfamily - a large group of structurally related and evolutionarily conserved proteins - profoundly shapes and organizes the vasculature during normal development and adult homeostasis. Mutations inactivating several of its ligands, receptors, or signal transducers set off hereditary hemorrhagic telangiectasia (HHT), a disorder that causes capillary networks to form incorrectly. Drosha, an essential microRNA-processing enzyme, also interfaces with TGFß signal transducers, but its involvement in vascular conditions had not been tested until recently. This review summarizes current evidence that links mutations of Drosha to HHT. RECENT FINDINGS: Genetic studies have revealed that rare missense mutations in the Drosha gene occur more commonly among HHT patients than in healthy people. Molecular analyses also indicated that Drosha enzymes with HHT-associated mutations generate microRNAs less efficiently than their wild-type counterpart when stimulated by TGFß ligands. In zebrafish or mouse, mutant Drosha proteins cause the formation of dilated, leaky blood vessels deprived of capillaries, similar to those typically found in patients with HHT. SUMMARY: Recent evidence suggests that Drosha-mediated microRNA biogenesis contributes significantly to the control of vascular development and homeostasis by TGFß. Loss or reduction of Drosha function may predispose carriers to HHT and possibly other vascular diseases.

Associations of dietary diversity with allergic diseases in Japanese workers: a cross-sectional study.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the associations of dietary diversity with prevalences of allergic diseases. METHODS AND STUDY DESIGN: The participants were 1,317 men and women aged 20 to 63 years who were living in Tokushima Prefecture, Japan during the period 2012-2013. We obtained anthropometric data and information on lifestyle characteristics and current medical histories of allergic diseases using a self-administered questionnaire. Dietary intake was assessed using a food frequency questionnaire, and dietary diversity was determined using the Quantitative Index for Dietary Diversity (QUANTIDD). The ORs and 95% CIs for each of the allergic diseases with a 1 standard deviation (SD) increase in the QUANTIDD score were estimated, controlling for age, family history of allergic diseases, education, smoking, drinking, physical activity, energy intake and BMI. RESULTS: Higher dietary diversity showed significant inverse dose-response relationships with allergic diseases and allergic rhinitis in women. Multivariate-adjusted ORs (95% CI) for allergic diseases and allergic rhinitis with 1 SD increase in the QUANTIDD score were 0.77 (95% CI: 0.60-0.98, p=0.037) and 0.69 (95% CI: 0.53-0.90, p=0.007), respectively, in women. There were no significant associations between dietary diversity and allergic diseases in men. CONCLUSIONS: The results indicate that there is an inverse association between higher dietary diversity and allergic rhinitis in Japanese female workers.

Dysregulation of microRNA biogenesis machinery in cancer.

MicroRNAs (miRNAs) are integral to the gene regulatory network. A single miRNA is capable of controlling the expression of hundreds of protein coding genes and modulate a wide spectrum of biological functions, such as proliferation, differentiation, stress responses, DNA repair, cell adhesion, motility, inflammation, cell survival, senescence and apoptosis, all of which are fundamental to tumorigenesis. Overexpression, genetic amplification, and gain-of-function mutation of oncogenic miRNAs ("onco-miRs") as well as genetic deletion and loss-of-function mutation of tumor suppressor miRNAs ("suppressor-miRs") are linked to human cancer. In addition to the dysregulation of a specific onco-miR or suppressor-miRs, changes in global miRNA levels resulting from a defective miRNA biogenesis pathway play a role in tumorigenesis. The function of individual onco-miRs and suppressor-miRs and their target genes in cancer has been described in many different articles elsewhere. In this review, we primarily focus on the recent development regarding the dysregulation of the miRNA biogenesis pathway and its contribution to cancer.

Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells. However, the mechanisms underlying alterations in energy production have not been identified. METHODS: Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and patients with idiopathic PAH to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from patients with PAH, the downregulation of microRNA-124 (miR-124), determined with a tiered systems biology approach, is responsible for increased expression of the splicing factor PTBP1 (polypyrimidine tract binding protein), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells. RESULTS: Heritable PAH and idiopathic PAH BOECs recapitulated the metabolic abnormalities observed in pulmonary artery endothelial cells from patients with idiopathic PAH, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124 or siRNA silencing of PTPB1 restored normal proliferation and glycolysis in heritable PAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration. BMPR2 knockdown in control BOECs reduced the expression of miR-124, increased PTPB1, and enhanced glycolysis. Moreover, we observed reduced miR-124, increased PTPB1 and PKM2 expression, and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced BMPR2 expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo. CONCLUSIONS: Pulmonary vascular and circulating progenitor endothelial cells isolated from patients with PAH demonstrate downregulation of miR-124, leading to the metabolic and proliferative abnormalities in PAH ECs via PTPB1 and PKM1/PKM2. Therefore, the manipulation of this miRNA or its targets could represent a novel therapeutic approach for the treatment of PAH.

Analysis of the microRNA signature driving adaptive right ventricular hypertrophy in an ovine model of congenital heart disease.

The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs ( n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha.

The signal transducers of the transforming growth factor beta (TGFbeta)/bone morphogenetic protein (BMP), the Smads, promote the expression of a subset of miRNAs by facilitating the cleavage reaction by Drosha. The mechanism that limits Smad-mediated processing to a selective group of miRNAs remained hitherto unexplored. In this study, we expand the number of TGFbeta/BMP-regulated miRNAs (T/B-miRs) to 20. Of interest, a majority of T/B-miRs contain a consensus sequence (R-SBE) within the stem region of the primary transcripts of T/B-miRs (pri-T/B-miRs). Here, we demonstrate that Smads directly bind the R-SBE. Mutation of the R-SBE abrogates TGFbeta/BMP-induced recruitment of Smads, Drosha, and DGCR8 to pri-T/B-miRs and impairs their processing, whereas introduction of R-SBE to unregulated pri-miRNAs is sufficient to recruit Smads and to allow regulation by TGFbeta/BMP. Thus, Smads are multifunctional proteins that modulate gene expression transcriptionally through DNA binding and posttranscriptionally through pri-miRNA binding and regulation of miRNA processing.

The role of TGF-ß superfamily signaling in neurological disorders.

The TGF-ß superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-ß superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-ßs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-ß superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-ß/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-ß/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-ß/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature.

Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators.

Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress.

It is widely accepted that different forms of stress activate a common target, p53, yet different outcomes are triggered in a stress-specific manner. For example, activation of p53 by genotoxic agents, such as camptothecin (CPT), triggers apoptosis, while non-genotoxic activation of p53 by Nutlin-3 (Nut3) leads to cell-cycle arrest without significant apoptosis. Such stimulus-specific responses are attributed to differential transcriptional activation of various promoters by p53. In this study, we demonstrate that CPT, but not Nut3, induces miR-203, which downregulates anti-apoptotic bcl-w and promotes cell death in a p53-dependent manner. We find that acetylation of K120 in the DNA-binding domain of p53 augments its association with the Drosha microprocessor and promotes nuclear primary miRNA processing. Knockdown of human orthologue of Males absent On the First (hMOF), the acetyltransferase that targets K120 in p53, abolishes induction of miR-203 and cell death mediated by CPT. Thus, this study reveals that p53 acetylation at K120 plays a critical role in the regulation of the Drosha microprocessor and that post-transcriptional regulation of gene expression by p53 via miRNAs plays a role in determining stress-specific cellular outcomes.

Functions of microRNAs in cardiovascular biology and disease.

In 1993, lin-4 was discovered as a critical modulator of temporal development in Caenorhabditis elegans and, most notably, as the first in the class of small, single-stranded noncoding RNAs now defined as microRNAs (miRNAs). Another eight years elapsed before miRNA expression was detected in mammalian cells. Since then, explosive advancements in the field of miRNA biology have elucidated the basic mechanism of miRNA biogenesis, regulation, and gene-regulatory function. The discovery of this new class of small RNAs has augmented the complexity of gene-regulatory programs as well as the understanding of developmental and pathological processes in the cardiovascular system. Indeed, the contributions of miRNAs in cardiovascular development and function have been widely explored, revealing the extensive role of these small regulatory RNAs in cardiovascular physiology.

Palmitate-stimulated monocytes induce adhesion molecule expression in endothelial cells via IL-1 signaling pathway.

Increased intake of saturated fatty acids (SFAs), such as palmitate (Pal), is linked to a higher risk of type 2 diabetes and cardiovascular disease. Although recent studies have investigated the direct effects of SFAs on inflammatory responses in vascular endothelial cells, it remains unknown whether SFAs also induce these responses mediated by circulating cells. In this study, especially focused on adhesion molecules and monocytes, we investigated the indirect effects of Pal on expression and release of ICAM-1 and E-selectin in vascular endothelial cells. Phorbol 12-myristate 13-acetate (PMA)-treated THP-1 (pTHP-1) cells and human monocytes were stimulated with various free fatty acids (FFAs). SFAs, but not unsaturated fatty acids (UFAs), increased interleukin (IL)-1ß secretion and decreased IL-1 receptor antagonist (IL-1Ra) secretion, resulting in an increase in the IL-1ß/IL-1Ra secretion ratio. UFAs dose-dependently inhibited the increase in IL-1ß secretion and decrease in IL-1Ra secretion induced by Pal. Moreover, in human aortic and vein endothelial cells, expression and release of ICAM-1 and E-selectin were induced by treatment with conditioned medium collected from Pal-stimulated pTHP-1 cells and human monocytes, but not by Pal itself. The up-regulated expression and release of adhesion molecules by the conditioned medium were mostly abolished by recombinant human IL-1Ra supplementation. These results suggest that the Pal-induced increase in the ratio of IL-1ß/IL-1Ra secretion in monocytes up-regulates endothelial adhesion molecules, which could enhance leukocyte adhesion to endothelium. This study provides further evidence that IL-1ß neutralization through receptor antagonism may be useful for preventing the onset and development of cardiovascular disease.

A taste of TGFß in Tuscany.

The recent FASEB Summer Research Conference entitled 'The TGFß Superfamily: Signaling in Development and Disease' was held in August, 2011 in the spectacular setting of Il Ciocco, Lucca, amidst the olive trees in Tuscany, Italy. The organizers assembled an amazing forum, which included 53 speakers and 67 poster presentations from laboratories around the world, to showcase recent advances made in our understanding of the transforming growth factor-ß (TGFß) signaling pathway.

Therapeutic Ultrasound Promotes Reperfusion and Angiogenesis in a Rat Model of Peripheral Arterial Disease.

BACKGROUND: Shock wave therapy (SWT) is an acoustic technology clinically used for the non-invasive treatment of ischemic heart disease (IHD). Therapeutic ultrasound (TUS) has more recently been developed for the same indication, although its effects on reperfusion and angiogenesis have yet to be directly compared to those of SWT. METHODS AND RESULTS: TUS and SWT acoustic parameters were matched, and their ability to promote angiogenesis and reperfusion in a rat hindlimb ischemia model was compared. After left femoral artery excision, 3-weekly TUS, SWT or sham treatments (n=10 rats each) of the left hindlimb were performed for 2 weeks. Laser Doppler perfusion imaging demonstrated improved perfusion with TUS (66±4% L:R hindlimb perfusion, mean±SEM, P=0.02), but not with SWT (59±4%, P=0.13) compared with sham (50±4%). Immunohistochemistry of CD31 demonstrated increased microvascular density with TUS (222.6 vessels/high-power field, P=0.001) and SWT (216.9, P=0.01) compared to sham-treated rats (196.0). Tissue vascular endothelial growth factor mRNA levels were elevated in the left hindlimb of TUS-, but not SWT- or sham-treated rats. CONCLUSIONS: Direct comparison demonstrates that TUS is more effective than SWT at promoting reperfusion, whereas both therapies promote angiogenesis in ischemic gastrocnemius muscle. These results suggest that TUS may be more effective than SWT for the treatment of IHD and peripheral arterial disease.

Down-regulation of miR-96 by bone morphogenetic protein signaling is critical for vascular smooth muscle cell phenotype modulation.

The bone morphogenetic protein (BMP) signaling pathway is critical for the induction and maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). Inactivation of BMP signaling is common in abnormalities in vascular development and in vascular proliferative conditions, such as pulmonary artery hypertension. Herein, we identify microRNA-96 (miR-96) as a modulator of the VSMC phenotype in response to BMP4 signaling. We show that miR-96 is down-regulated by BMP4 treatment, which results in the derepression of a novel target, Tribbles-like protein 3 (Trb3). miR-96 targets a partially complementary sequence localized in the 3' UTR of Trb3. Trb3 is an essential positive regulator of the BMP signaling pathway and promotes contractile phenotype in VSMCs. In conclusion, our study demonstrates a novel mechanism of regulation of SMC-specific gene expression and induction of a VSMC contractile phenotype by the BMP4 signaling pathway via suppression of the miR-96-Trb3 axis.

Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.

Modulation of the vascular smooth-muscle-cell (vSMC) phenotype from a quiescent 'contractile' phenotype to a proliferative 'synthetic' phenotype has been implicated in vascular injury repair, as well as pathogenesis of vascular proliferative diseases. Both bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta)-signalling pathways promote a contractile phenotype, while the platelet-derived growth factor-BB (PDGF-BB)-signalling pathway promotes a switch to the synthetic phenotype. Here we show that PDGF-BB induces microRNA-24 (miR-24), which in turn leads to downregulation of Tribbles-like protein-3 (Trb3). Repression of Trb3 coincides with reduced expression of Smad proteins and decrease in BMP and TGFbeta signalling, promoting a synthetic phenotype in vSMCs. Inhibition of miR-24 by antisense oligonuclotides abrogates the downregulation of Trb3 as well as pro-synthetic activity of the PDGF-signalling pathway. Thus, this study provides a molecular basis for the antagonism between the PDGF and TGFbeta pathways, and its effect on the control of the vSMC phenotype.

SMAD proteins control DROSHA-mediated microRNA maturation.

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.

Long-term impact of COVID-19 pandemic on secular changes in metabolic parameters in Japanese workers : Tokushima Cohort Study.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented changes in people's lifestyles. Since then, our lifestyle has remained different from what it used to be in the pre-pandemic era. This study investigated the long-term impact of the COVID-19 pandemic on secular changes in metabolic parameters in Japanese workers. METHODS: A total of 519 eligible subjects completed fiscal year (FY) 2017, FY2019 and FY2021 surveys. Comparison between pre-COVID-19 (Δpre-covid19 : FY2019-2017) and during COVID-19 (Δcovid19 : FY2021-2019) was performed in each sex. RESULTS: Increment of diastolic blood pressure (DBP) in Δcovid19 was significantly greater than that in Δpre-covid19 (Δpre-covid19 to Δcovid19 : 0.22 ± 6.17 to 2.59 ± 6.69 mmHg, p = 0.0002 in males, -0.18 ± 6.26 to 2.16 ± 6.60 mmHg, p = 0.01 in females). In females, increments of waist circumference and fasting plasma glucose in Δcovid19 were also significantly greater than those in Δpre-covid19 (both p < 0.05). Conversely, increments of BMI and body fat in Δcovid19 were significantly smaller than those in Δpre-covid19 in males (both p < 0.05). CONCLUSION: Our findings suggest that there was an apparent metabolic impact of the COVID-19 pandemic on DBP increment in Japanese workers. In addition, COVID-19 may have influenced males and females differently in relation to glucose metabolism and anthropometric measurements related to obesity / adiposity. J. Med. Invest. 71 : 47-53, February, 2024.