RATIONALE:Heart failure (HF) and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33 is considered as a potential ...therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in HF remains to be elucidated.
OBJECTIVE:To clarify the role of miR-33 involved in HF.
METHODS AND RESULTS:We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33-deficient (KO) mice. When mice were subjected to TAC, miR-33 expression levels were significantly up-regulated in wild-type (WT) left ventricles. There was no difference in hypertrophic responses between WT and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with WT hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after TAC. We also found that cardiac fibroblasts (CFs) were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired CF proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, CF-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by TAC as systemic miR-33KO mice.
CONCLUSIONS:Our results demonstrate that miR-33 is involved in cardiac remodeling and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.
Masahiro Mori is a well-known Japanese robotics scholar whose notion of Uncanny Valley is worldly famous. Mori is also an initiator of the Robot Contest and a student of Buddhism and a practitioner ...of Zen. He constructs his original Buddhist philosophy of robotics throughout his career. His robotics work and his learning of Buddhism develop together side by side in an interesting intertwined manner. This paper will take up the issues such as the ethical personality, quality of minds, and experiences of engineers as key components in and for an “ethical design” of robots by examining Mori’s Buddhist philosophy of robotics. This paper is divided into four sections. After an introductory part, in the second section, we will explore Mori’s view of Zen as aspiritual source for technological creativity. In Section 3, we will examine his view into a robot-contest as a location of a realized teaching of Buddhism, especially, in relationship to the Diamond Sūtra, in order to see Mori’s educational contribution. In Section 4, we will examine how Mori became engaged to learn and practice Buddhism and came to the realization of Buddhahood in relation to robotics.
Protein-coding genes account for less than 2% of the whole genome. However, the advances in RNA sequencing and genome-wide analysis have demonstrated that most of the genome is capable of being ...transcribed. Moreover, recent studies have suggested that long non-coding RNAs (lncRNAs) are critical regulators of gene expression and epigenesis in both physiological and disease states. Several lncRNAs are functionally involved in cardiovascular diseases and may be potential therapeutic targets. Here, we review the current strategies for the discovery of functional lncRNAs and recently discovered lncRNAs in the cardiovascular field, focusing on cardiac development, hypertrophy, heart failure, and atherosclerosis. We also discuss the therapeutic potentials of synthetic RNAs to modulate these lncRNAs and future directions in this research field.
The Cre-LoxP system has been commonly used for cell-specific genetic manipulation. However, many Cre strains exhibit excision activity in unexpected cell types or tissues. Therefore, it is important ...to identify the cell types in which recombination takes place. Fibroblasts are a cell type that is inadequately defined due to a lack of specific markers to detect the entire cell lineage. Here, we investigated the Cre recombination induced by Col1α2-iCre, one of the most common fibroblast-mesenchymal Cre driver lines, by using a double-fluorescent Cre reporter line in which GFP is expressed when recombination occurs. Our results indicated that Col1α2-iCre activity was more extensive across cell types than previously reported: Col1α2-iCre-mediated recombination was found in not only cells of mesenchymal origin but also those of other lineages, including haematopoietic cells, myocardial cells, lung and intestinal epithelial cells, and neural cells. In addition, study of embryos revealed that recombination by Col1α2-iCre was observed in the early developmental stage before gastrulation in epiblasts, which would account for the recombination across various cell types in adult mice. These results offer more insights into the activity of Col1α2-iCre and suggest that experimental results obtained using Col1α2-iCre should be carefully interpreted.
Deep low-frequency tremors and short-term slow slip events (SSEs) are known to occur along the Nankai Trough in Japan. Although short-term SSEs are thought to occur repeatedly in the northern part of ...Ise Bay, deep low-frequency tremors are not observed there. Because the area around the northern part of Ise Bay is characterized by soft sedimentary layers not suitable for strainmeter or tiltmeter installation, there are no high-quality crustal deformation observation sites in the area. Accordingly, the local extent of slip of short-term SSEs has not been confirmed. We significantly improved the crustal strain sensitivity of the groundwater level (pressure) in the inner pipe of the observation well at the Hokusei observation site (HKSi, northwest of Ise Bay) by sealing it with a packer. Consequently, we were able to observe groundwater pressure changes related to slow slip at the plate boundary. We estimate that slip of short-term SSEs during July 2016, November 2017, and April 2018 extended to the northern part of Ise Bay. Furthermore, groundwater pressure fluctuations at HKSi in April 2018 greatly improved the SSE fault model, confirming that slow slip occurs in the area, despite the absence of deep low-frequency tremor. The slips without tremors are a characteristic of the northern area of Ise Bay, differing from other areas of the Nankai Trough. Our results demonstrate that groundwater level/pressure fluctuations are a powerful tool for crustal deformation observations in areas characterized by soft sedimentary layers.
The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the ...utility of the DAPT score in the Japanese population.
In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto Coronary Revascularization Demonstrating Outcome Study in Kyoto Registry Cohort-2, RESET Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial, and NEXT NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score <2 (low DS).
Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%,
=0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%,
=0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%,
=0.03; 1.5% versus 0.8%,
=0.002; 0.7% versus 0.3%,
<0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%,
<0.001; 1.0% versus 1.6%,
=0.03, respectively).
In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.
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