Heart failure 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 heart failure remains to be elucidated.
To clarify the role of miR-33 involved in heart failure.
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 in miR-33-deficient (knockout KO) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.
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.
Objective- Atherosclerosis is a common disease caused by a variety of metabolic and inflammatory disturbances. MicroRNA (miR)-33a within SREBF2 (sterol regulatory element-binding factor 2) is a ...potent target for treatment of atherosclerosis through regulating both aspects; however, the involvement of miR-33b within SREBF1 remains largely unknown. Although their host genes difference could lead to functional divergence of miR-33a/b, we cannot dissect the roles of miR-33a/b in vivo because of lack of miR-33b sequences in mice, unlike human. Approach and Results- Here, we analyzed the development of atherosclerosis using miR-33b knock-in humanized mice under apolipoprotein E-deficient background. MiR-33b is prominent both in human and mice on atheroprone condition. MiR-33b reduced serum high-density lipoprotein cholesterol levels and systemic reverse cholesterol transport. MiR-33b knock-in macrophages showed less cholesterol efflux capacity and higher inflammatory state via regulating lipid rafts. Thus, miR-33b promotes vulnerable atherosclerotic plaque formation. Furthermore, bone marrow transplantation experiments strengthen proatherogenic roles of macrophage miR-33b. Conclusions- Our data demonstrated critical roles of SREBF1-miR-33b axis on both lipid profiles and macrophage phenotype remodeling and indicate that miR-33b is a promising target for treating atherosclerosis.
MicroRNA 33 (miR-33) targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum high-density lipoprotein (HDL)-cholesterol (HDL-C) and ameliorates atherosclerosis. ...Although we previously reported that miR-33 deficiency increased peripheral Ly6C
high
monocytes on an ApoE-deficient background, the effect of miR-33 on the monocyte population has not been fully elucidated, especially in a wild-type (WT) background. We found that Ly6C
high
monocytes in miR-33
−/−
mice were decreased in peripheral blood and increased in bone marrow (BM). Expansion of myeloid progenitors and decreased apoptosis in Lin
−
Sca1
+
c-Kit
+
(LSK) cells were observed in miR-33
−/−
mice. A BM transplantation study and competitive repopulation assay revealed that hematopoietic miR-33 deficiency caused myeloid expansion and increased peripheral Ly6C
high
monocytes and that nonhematopoietic miR-33 deficiency caused reduced peripheral Ly6C
high
monocytes. Expression of high-mobility group AT-hook 2 (HMGA2) targeted by miR-33 increased in miR-33-deficient LSK cells, and its knockdown abolished the reduction of apoptosis. Transduction of human apolipoprotein A1 and ABCA1 in WT mouse liver increased HDL-C and reduced peripheral Ly6C
high
monocytes. These data indicate that miR-33 deficiency affects distribution of inflammatory monocytes through dual pathways. One pathway involves the enhancement of Hmga2 expression in hematopoietic stem cells to increase Ly6C
high
monocytes, and the other involves the elevation of HDL-C to decrease peripheral Ly6C
high
monocytes.
Acute cardiac rupture and adverse left ventricular (LV) remodeling causing heart failure are serious complications of acute myocardial infarction (MI). While cardio-hepatic interactions have been ...recognized, their role in MI remains unknown. We treated cultured cardiomyocytes with conditioned media from various cell types and analyzed the media by mass spectrometry to identify α1-microglobulin (AM) as an Akt-activating hepatokine. In mouse MI model, AM protein transiently distributed in the infarct and border zones during the acute phase, reflecting infiltration of AM-bound macrophages. AM stimulation activated Akt, NFκB, and ERK signaling and enhanced inflammation as well as macrophage migration and polarization, while inhibited fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts. Intramyocardial AM administration exacerbated macrophage infiltration, inflammation, and matrix metalloproteinase 9 mRNA expression in the infarct and border zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in MI. Shotgun proteomics and lipid pull-down analysis found that AM partly binds to phosphatidic acid (PA) for its signaling and function. Furthermore, systemic delivery of a selective inhibitor of diacylglycerol kinase α-mediated PA synthesis notably reduced macrophage infiltration, inflammation, matrix metalloproteinase activity, and adverse LV remodeling in MI. Therefore, targeting AM signaling could be a novel pharmacological option to mitigate adverse LV remodeling in MI.
MicroRNA 33 (miR-33) targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum high-density lipoprotein (HDL)-cholesterol (HDL-C) and ameliorates atherosclerosis. ...Although we previously reported that miR-33 deficiency increased peripheral Ly6C
monocytes on an ApoE-deficient background, the effect of miR-33 on the monocyte population has not been fully elucidated, especially in a wild-type (WT) background. We found that Ly6C
monocytes in miR-33
mice were decreased in peripheral blood and increased in bone marrow (BM). Expansion of myeloid progenitors and decreased apoptosis in Lin
Sca1
c-Kit
(LSK) cells were observed in miR-33
mice. A BM transplantation study and competitive repopulation assay revealed that hematopoietic miR-33 deficiency caused myeloid expansion and increased peripheral Ly6C
monocytes and that nonhematopoietic miR-33 deficiency caused reduced peripheral Ly6C
monocytes. Expression of high-mobility group AT-hook 2 (HMGA2) targeted by miR-33 increased in miR-33-deficient LSK cells, and its knockdown abolished the reduction of apoptosis. Transduction of human apolipoprotein A1 and ABCA1 in WT mouse liver increased HDL-C and reduced peripheral Ly6C
monocytes. These data indicate that miR-33 deficiency affects distribution of inflammatory monocytes through dual pathways. One pathway involves the enhancement of
expression in hematopoietic stem cells to increase Ly6C
monocytes, and the other involves the elevation of HDL-C to decrease peripheral Ly6C
monocytes.
Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support ...cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.
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•Glutamine-deprived cancer cells are rich in phosphoethanolamine (PEtn)•PEtn stimulates tolerance to nutrient starvation and tumor growth•PCYT2 inhibition triggers PEtn accumulation during glutamine deprivation•PCYT2 downregulation is associated with poor prognosis for breast cancer patients
Osawa et al. find that accumulation of phosphoethanolamine (PEtn) protects cancer cells under glutamine starvation through the downregulation of PCYT2. Glutamine regulates PE biosynthesis through PCYT2, resulting in pro-tumorigenic metabolite PEtn accumulation. PEtn stimulates the tolerance of cancer cells to starvation, and lowered PCYT2 expression correlates with decreased survival in patients.
Several in vivo studies suggest that nanoparticles (smaller than 100 nm) have the ability to reach the brain tissue. Moreover, some nanoparticles can penetrate into the brains of murine fetuses ...through the placenta by intravenous administration to pregnant mice. However, it is not clear whether the penetrated nanoparticles affect neurogenesis or brain function. To evaluate its effects on neural stem cells, we assayed a human neural stem cell (hNSCs) line exposed in vitro to three types of silica particles (30 nm, 70 nm, and <44 µm) and two types of titanium oxide particles (80 nm and < 44 µm). Our results show that hNSCs aggregated and exhibited abnormal morphology when exposed to the particles at concentrations = 0.1 mg/mL for 7 days. Moreover, all the particles affected the gene expression of Nestin (stem cell marker) and neurofilament heavy polypeptide (NF-H, neuron marker) at 0.1 mg/mL. In contrast, only 30-nm silica particles at 1.0 mg/mL significantly reduced mitochondrial activity. Notably, 30-nm silica particles exhibited acute membrane permeability at concentrations =62.5 µg/mL in 24 h. Although these concentrations are higher than the expected concentrations of nanoparticles in the brain from in vivo experiments in a short period, these thresholds may indicate the potential toxicity of accumulated particles for long-term usage or continuous exposure.
We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential ...hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.
Objectives: Dental caries prevention programs using chlorhexidine (CHX) have been proposed, but CHX's effect in reducing levels of mutans streptococci (S. mutans and S. sobrinus) appears to last for ...only a few months. The aim of this study was to attempt to eradicate mutans streptococci from the oral cavity using intensive professional mechanical tooth cleaning (PMTC) and topical application of CHX in custom-made trays. Methods: Seven adult dentate subjects participated in this study (mean age 53.7 +/− 5.6, age range 46 to 62, mean DMFT, 9.1 +/− 4.2). For each subject, PMTC was carried out eight times within ten days. After each PMTC, 1% CHX was applied twice to the tooth surface using custom-made trays. In addition, as home treatment, subjects were required to carry out tooth brushing three times a day, and apply 0.2% CHX in custom trays after brushing in the morning and evening. In addition, subjects rinsed with 0.2% CHX solution after lunch. Salivary levels of mutans streptococci were evaluated using Dentocult-SM at baseline and on days 9, 20, 70, 120. Results: Mutans streptococci were eradicated by day 120 from 4 of the 7 seven subjects participating in this study. Those 3 subjects still harboring mutans streptococci exhibited deep periodontal pocketing. Conclusions: Eradication of mutans streptococci from the oral cavity is feasible using a combination of CHX application in custom-made trays and intensive PMTC. (J. Oral Sci. 46, 179-183, 2004)
We investigated biapenem (BIPM, L-627) a newly carbapenem antibiotic, for its antibacterial activity, tissue penetration, clinical efficacy and bacteriological effect in obstetric and gynecological ...infections, and obtained the following results. 1. Antibacterial activity: MICs of L-627 against 149 strains isolated from 80 patients in this clinical trial were examined and compared with those of imipenem (IPM) and ceftazidime (CAZ). The MIC50 and MIC90 of L-627 against the isolates were 0.2 and 12.5 micrograms/ml, respectively. Those of IPM were 0.2 and 6.25 micrograms/ml, respectively. The antibacterial activity of L-627 was quite similar to that of IPM, and was superior to that of CAZ. 2. Tissue and retroperitoneal fluid penetration: The peak levels in venous and uterine arterial sera were 24.0 and 26.2 micrograms/ml, respectively, after 300 mg drip infusion. The peak levels in the uterine or adnexal tissues were 2.39-9.60 micrograms/g, and 0.2 microgram/g of L-627 was detected at 275 minutes after administration. Peak levels in retroperitoneal fluid were 8.7 +/- 1.7 micrograms/ml at 1 hour after the completion of 30 minutes drip infusion (300 mg) and 7.9 +/- 0.2 micrograms/ml at 30 minutes after 300 mg 60 minutes drip infusion (300 mg). These levels expected the MICs against main pathogenic organisms. 3.
L-627 was given to the following 144 patients (No. of analytical subjects) at a daily dose of 0.3-1.2 g for 2-13 days: intrauterine infections (54), adnexitis (36), parametritis (17), pelvic peritonitis (27), bartholins abscess (6) and other infections (4). The clinical efficacy was 93.1% (134/144) and the eradication rate against isolated organisms was 88.7% (110/124). Side effects were observed in 2 patients: eruption (1) and vomiting with numbness of the tongue (1). Abnormal change in laboratory test results included increase in eosinophils in 1, increase in GOT, GPT and gamma-GTP in 1 and increase in GPT and A1-P in 1, but all of these abnormalities were very mild and withdrawal of the drug was not required. Our results suggest that this drug is useful in the treatment of gynecological infections.
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