Circulating exosomal mir-16-2-3p is associated with coronary microvascular dysfunction in diabetes through regulating the fatty acid degradation of endothelial cells.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a frequent complication of diabetes mellitus (DM) characterized by challenges in both diagnosis and intervention. Circulating levels of microRNAs are increasingly recognized as potential biomarkers for cardiovascular diseases. METHODS: Serum exosomes from patients with DM, DM with coronary microvascular dysfunction (DM-CMD) or DM with coronary artery disease (DM-CAD) were extracted for miRNA sequencing. The expression of miR-16-2-3p was assessed in high glucose-treated human aortic endothelial cells and human cardiac microvascular endothelial cells. Fluorescence in situ hybridization (FISH) was used to detect miR-16-2-3p within the myocardium of db/db mice. Intramyocardial injection of lentivirus overexpressing miR-16-2-3p was used to explore the function of the resulting gene in vivo. Bioinformatic analysis and in vitro assays were carried out to explore the downstream function and mechanism of miR-16-2-3p. Wound healing and tube formation assays were used to explore the effect of miR-16-2-3p on endothelial cell function. RESULTS: miR-16-2-3p was upregulated in circulating exosomes from DM-CMD, high glucose-treated human cardiac microvascular endothelial cells and the hearts of db/db mice. Cardiac miR-16-2-3p overexpression improved cardiac systolic and diastolic function and coronary microvascular reperfusion. In vitro experiments revealed that miR-16-2-3p could regulate fatty acid degradation in endothelial cells, and ACADM was identified as a potential downstream target. MiR-16-2-3p increased cell migration and tube formation in microvascular endothelial cells. CONCLUSIONS: Our findings suggest that circulating miR-16-2-3p may serve as a biomarker for individuals with DM-CMD. Additionally, miR-16-2-3p appears to alleviate coronary microvascular dysfunction in diabetes by modulating ACADM-mediated fatty acid degradation in endothelial cells.

Metformin reduces new-onset atrial fibrillation risk rather than atrial fibrillation burden in type 2 diabetes patients: A case-control study.

Background: The effects of metformin on atrial fibrillation (AF) in type 2 diabetes patients remain unclear. We aimed to explore the effects of metformin on AF, including new-onset AF and AF burden, in type 2 diabetes patients with pacemakers. Methods and results: This retrospective study included a total of 227 patients. Based on the presence of paroxysmal AF, the patients were divided into a paroxysmal AF group (n = 80) and a non-AF group (n = 147). In the non-AF group, a significant association was observed between metformin use and a lower risk of new-onset AF in multivariable Cox hazards models (hazard ratio [HR]: 0.36; 95 % confidence interval [CI]: 0.14-0.91; p = 0.0311*) when adjusted for age, sex, body mass index (BMI), drinking, smoking, left atrial dimension, creatinine, complications, and drugs. In the paroxysmal AF group, univariable analysis indicated no association between the AF burden and metformin use (p = 0.817). Furthermore, when adjusted for metformin use, age, sex, BMI, drinking, smoking, cardiovascular disease, myocardial infarction, heart failure, stroke, and ejection fraction in multivariable Cox hazards models, we found a lower proportion of major adverse cardiovascular events (MACEs) both in the total (HR: 0.28; 95 % CI: 0.1-0.82; p = 0.0202*) and the non-AF group (HR: 0.19; 95 % CI: 0.05-0.79; p = 0.0223*) compared to that in the AF group (HR: 0.31; 95 % CI: 0.02-4.41; p = 0.3879). Conclusion: In type 2 diabetes patients with pacemakers, metformin reduced the probability of new-onset AF instead of addressing the AF burden. Furthermore, metformin therapy decreased the incidence of MACEs in type 2 diabetes patients without AF.

M2-like macrophages transplantation protects against the doxorubicin-induced heart failure via mitochondrial transfer.

AIMS: The alternatively activated macrophages have shown a cardioprotective effect in heart failure. However, the effect of M2 adoptive transfer in non-ischemic heart failure is unknown. In this study, we evaluated the efficacy of M-CSF plus IL-4 induced M2-like macrophages transplantation in doxorubicin-induced cardiotoxicity. METHODS: Bone marrow mononuclear cells were polarized as CCR2+CD206+ M2-like macrophages by a combination of M-CSF plus IL-4 treatment. C57BL/6 mice received a single intraperitoneal injection of doxorubicin (15 mg/kg). The treatment group were treated with M2-like macrophages (1 × 10^6 cells per mouse; i.v.) once a week for 2 weeks. After 3 weeks, we examined the percentage of resident cells and cardiac function. Furthermore, we evaluated cardiac fibrosis, cardiomyocyte apoptosis and circulating inflammatory factors. Finally, we investigated the mitochondria transfer in vitro in a direct and indirect co-culture conditions. RESULTS: Cardiac function was significantly improved in doxorubicin-induced heart failure by adoptive transfer of M2-like macrophages. Besides, M2-like macrophages treatment attenuated cardiac fibrosis and cardiomyocyte apoptosis, as well as increased the level of circulating IL-4 and Th2 response. In vitro, M2-like macrophages could transfer mitochondria to injured cardiomyocytes in a direct and indirect way. CONCLUSIONS: In our study, adoptive transfer of M2-like macrophages could protect against the doxorubicin-induced cardiotoxicity, which may be partly attributed to mitochondria transfer. And M2-like macrophages transplantation could become a treatment for non-ischemic heart failure in the clinical practice.

The impact of Sacubitril/Valsartan on cardiac fibrosis early after myocardial infarction in hypertensive rats.

BACKGROUND: Sacubitril/Valsartan, a dual inhibitor of the neprilysin and angiotensin receptor, exerts cardioprotective effects in heart failure. Little is known on the impact of Sacubitril/Valsartan in hypertensive patients early post myocardial infarction. METHODS: Spontaneously hypertensive rats (SHR) were pretreated by daily angiotensin receptor blocker (ARB; 30 mg/kg intraperitoneally), Sacubitril/Valsartan (ARNI; 60 mg/kg intraperitoneally) or the same dosage of physiological saline for 1 week. Then each group underwent myocardial infarction induction and received the same treatment for another week. The blood pressure and cardiac function were evaluated prior to sacrifice. We performed histological and molecular evaluation of fibrosis in vivo and in vitro. RESULTS: The blood pressure was comparable between three groups both 1 week prior to and post myocardial infarction. ARNI and ARB restore the decreased ejection fraction (57.3 ±â€Š7.6 vs. 42.9 ±â€Š5.2%, P < 0.05; 54.3 ±â€Š6.9 vs. 42.9 ±â€Š5.2%, P < 0.01, respectively) and fractional shortening (31.6 ±â€Š5.4 vs. 22.1 ±â€Š3.1%, P < 0.05; 29.4 ±â€Š4.5 vs. 22.1 ±â€Š3.1%, P < 0.05, respectively) post myocardial infarction. The infarct size and collagen deposition were also significantly mitigated in ARNI and ARB groups. In addition, ARNI and ARB treatment reduced the expression of cardiac remodeling-related factors, such as Bnp, α-SMA, Vimentin, and Col1a1 (all P < 0.05 vs. MI group). Finally, ARNI and ARB decreased the expression of α-SMA in cardiac fibroblasts treated with Ang II. CONCLUSION: In conclusion, pretreatment with ARNI maintained cardiac function and reduced myocardial fibrosis in myocardial infarction, probably prior to any anti-hypertensive effect.

Osteoporosis was associated with severe abdominal aortic calcification based on a cross-sectional study.

Abdominal aortic calcification and osteoporosis are age-related diseases. Based on a nationally representative US population, we concluded that osteoporosis may be independently associated with severe abdominal aortic calcification, which could improve our insights into the prevention and management of vascular disease. INTRODUCTION: Abdominal aortic calcification (AAC) and osteoporosis are age-related diseases and share similar pathological mechanisms. However, the association between osteoporosis and AAC is uncertain. METHODS: A total of 3134 participants with complete record of AAC score calculated from dual-energy X-ray absorptiometry (DXA) were enrolled from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. The diagnosis of osteoporosis was obtained from self-reported interview. The baseline covariates were compared between participants with and without osteoporosis. Multivariable logistic regression was performed to examine the association between abdominal aortic calcification and osteoporosis. RESULTS: Compared with those without osteoporosis, participants with osteoporosis had higher AAC scores. Osteoporosis was positively associated with higher odds of severe AAC (OR = 2.65; 95%CI, 1.89-3.71; P < 0.001), and the association was not altered (OR = 2.17; 95%CI, 1.23-3.83; P = 0.008) after adjusting for numerous covariates. CONCLUSIONS: Our findings suggest that osteoporosis may be independently associated with severe abdominal aortic calcification.

In situ measurements of intracellular thermal conductivity using heater-thermometer hybrid diamond nanosensors.

Understanding heat dissipation processes at nanoscale during cellular thermogenesis is essential to clarify the relationships between the heat and biological processes in cells and organisms. A key parameter determining the heat flux inside a cell is the local thermal conductivity, a factor poorly investigated both experimentally and theoretically. Here, using a nanoheater/nanothermometer hybrid made of a polydopamine encapsulating a fluorescent nanodiamond, we measured the intracellular thermal conductivities of HeLa and MCF-7 cells with a spatial resolution of about 200 nm. The mean values determined in these two cell lines are both 0.11 ± 0.04 W m-1 K-1, which is significantly smaller than that of water. Bayesian analysis of the data suggests there is a variation of the thermal conductivity within a cell. These results make the biological impact of transient temperature spikes in a cell much more feasible, and suggest that cells may use heat flux for short-distance thermal signaling.

Ultrasmall Fe(III)-Tannic Acid Nanoparticles To Prevent Progression of Atherosclerotic Plaques.

Macrophage accumulation is central to the pathogenesis of atherosclerotic plaques. Reducing macrophages in plaques is an appealing approach to attenuate the development of atherosclerosis. Chemodynamic therapy, specifically inhibiting hydrogen peroxide (H2O2)-rich cells in slightly acidic microenvironment, has emerged as a new method in tumor treatment. Herein, we manufactured ultrasmall dopamine-modified hyaluronic acid (HD)-stabilized Fe(III)-tannic acid nanoparticles (HFTNPs). HFTNPs can specifically accumulate in inflammatory macrophages in atherosclerotic plaques, provide brighter magnetic resonance images, promote reactive oxygen species (ROS) generation, and induce the death of inflammatory macrophages without damaging normal cells and tissues. In conclusion, HFTNPs have a tremendous potential as safe and effective diagnostic and therapeutic reagents for atherosclerosis.

Bright Dots and Smart Optical Microscopy to Probe Intracellular Events in Single Cells.

Probing intracellular events is a key step in developing new biomedical methodologies. Optical microscopy has been one of the best options to observe biological samples at single cell and sub-cellular resolutions. Morphological changes are readily detectable in brightfield images. When stained with fluorescent molecules, distributions of intracellular organelles, and biological molecules are made visible using fluorescence microscopes. In addition to these morphological views of cells, optical microscopy can reveal the chemical and physical status of defined intracellular spaces. This review begins with a brief overview of genetically encoded fluorescent probes and small fluorescent chemical dyes. Although these are the most common approaches, probing is also made possible by using tiny materials that are incorporated into cells. When these tiny materials emit enough photons, it is possible to draw conclusions about the environment in which the tiny material resides. Recent advances in these tiny but sufficiently bright fluorescent materials are nextly reviewed to show their applications in tracking target molecules and in temperature imaging of intracellular spots. The last section of this review addresses purely optical methods for reading intracellular status without staining with probes. These non-labeling methods are especially essential when biospecimens are thereafter required for in vivo uses, such as in regenerative medicine.

Protection of Mitochondria from Free Hydroxyls by Zn(7)- and Cd(7)- Metallothioneins.

Zn(7)- and Cd(7)-metallothioneins were prepared. Mitochondria were isolated from rat hearts. Mitochondria lipid fluidity, protein conformation and mobility were determined by using ESR spin label. Ca(2+)-Mg(2+)-ATPase activity and (45)Ca uptake activity were assayed. It was found that, after being damaged by hydroxyl radicals, mitochondria lipid fluidity and protein mobility decreased, protein conformation changed and mitochondria Ca(2+)-Mg(2+)-ATPase activity, (45)Ca uptake activity were inhibited. Both Zn(7)- and Cd(7)-metallothioneins could antagonize hydroxyl radicals and protect myocardial mitochondria. However, this effect of Zn(7)-metallothionein was stronger than that of Cd(7)-metallothionein, because the apo-metallothionein has about 10 000 fold higher affinity for Cd than for Zn, so, Zn(7)-metallothionein would release more Zn(2+). More reduced thiol groups would be revealed.