HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.

Circulating Non-coding RNAs and Cardiovascular Diseases.

The discovery of noncoding RNAs (ncRNAs) including short microRNAs, long ncRNAs and circular RNAs has broaden our knowledge about mammalian genomes and transcriptomes. A growing number of evidence on aberrantly regulated ncRNAs in cardiovascular diseases has indicated that ncRNAs are critical contributors to cardiovascular pathophysiology. Moreover, multiple recent studies have reported that ncRNAs can be detected in the bloodstream that differs between health subjects and diseased patients and some of them are remarkably stable. Although our knowledge about the origin and function of the circulating ncRNAs is still limited, these molecules have been regarded as promising noninvasive biomarker for risk stratification, diagnosis and prognosis of various cardiovascular diseases. In this chapter, we have described biological characteristics of circulating ncRNAs and discussed current trends and future prospects for the usage of circulating ncRNAs as biomarkers for common cardiovascular diseases.

Chitosan nonwoven fabric composited calcium alginate and adenosine diphosphate as a hemostatic bandage for acute bleeding wounds.

Acute bleeding following accidental injury is a leading cause of mortality. However, conventional hemostatic bandages impede wound healing by inducing excessive blood loss, dehydration, and adherence to granulation tissue. Strategies such as incorporating active hemostatic agents and implementing chemical modifications can augment the properties of these bandages. Nevertheless, the presence of remote thrombosis and initiators may pose risks to human health. Here, a hemostatic bandage was developed by physically combined chitosan nonwoven fabric, calcium alginate sponge, and adenosine diphosphate. The presented hemostatic bandage not only exhibits active and passive mechanisms for promoting clotting but also demonstrates excellent mechanical properties, breathability, ease of removal without causing damage to the wound bed or surrounding tissues, as well as maintaining an optimal moist environment conducive to wound healing. In vitro evaluation results indicated that the hemostatic bandage possesses favorable cytocompatibility with low levels of hemolysis. Furthermore, it effectively aggregates various blood cells while activating platelets synergistically to promote both extrinsic and intrinsic coagulation pathways. In an in vivo rat model study involving liver laceration and femoral artery injury scenarios, our developed hemostatic bandage demonstrated rapid clot formation capabilities along with reduced blood loss compared to commercially available fabrics.

Electrospun Biomimetic Periosteum Capable of Controlled Release of Multiple Agents for Programmed Promoting Bone Regeneration.

The effective repair of large bone defects remains a major challenge due to its limited self-healing capacity. Inspired by the structure and function of the natural periosteum, an electrospun biomimetic periosteum is constructed to programmatically promote bone regeneration using natural bone healing mechanisms. The biomimetic periosteum is composed of a bilayer with an asymmetric structure in which an aligned electrospun poly(ε-caprolactone)/gelatin/deferoxamine (PCL/GEL/DFO) layer mimics the outer fibrous layer of the periosteum, while a random coaxial electrospun PCL/GEL/aspirin (ASP) shell and PCL/silicon nanoparticles (SiNPs) core layer mimics the inner cambial layer. The bilayer controls the release of ASP, DFO, and SiNPs to precisely regulate the inflammatory, angiogenic, and osteogenic phases of bone repair. The random coaxial inner layer can effectively antioxidize, promoting cell recruitment, proliferation, differentiation, and mineralization, while the aligned outer layer can promote angiogenesis and prevent fibroblast infiltration. In particular, different stages of bone repair are modulated in a rat skull defect model to achieve faster and better bone regeneration. The proposed biomimetic periosteum is expected to be a promising candidate for bone defect healing.

Visible-Light Cross-Linkable Multifunctional Hydrogels Loaded with Exosomes Facilitate Full-Thickness Skin Defect Wound Healing through Participating in the Entire Healing Process.

The management of severe full-thickness skin defect wounds remains a challenge due to their irregular shape, uncontrollable bleeding, high risk of infection, and prolonged healing period. Herein, an all-in-one OD/GM/QCS@Exo hydrogel was prepared with catechol-modified oxidized hyaluronic acid (OD), methylacrylylated gelatin (GM), and quaternized chitosan (QCS) and loaded with adipose mesenchymal stem cell-derived exosomes (Exos). Cross-linking of the hydrogel was achieved using visible light instead of ultraviolet light irradiation, providing injectability and good biocompatibility. Notably, the incorporation of catechol groups and multicross-linked networks in the hydrogels conferred strong adhesion properties and mechanical strength against external forces such as tensile and compressive stress. Furthermore, our hydrogel exhibited antibacterial, anti-inflammatory, and antioxidant properties along with wound-healing promotion effects. Our results demonstrated that the hydrogel-mediated release of Exos significantly promotes cellular proliferation, migration, and angiogenesis, thereby accelerating skin structure reconstruction and functional recovery during the wound-healing process. Overall, the all-in-one OD/GM/QCS@Exo hydrogel provided a promising therapeutic strategy for the treatment of full-thickness skin defect wounds through actively participating in the entire process of wound healing.

Multi-crosslinked hydrogels with strong wet adhesion, self-healing, antibacterial property, reactive oxygen species scavenging activity, and on-demand removability for seawater-immersed wound healing.

In general, seawater-immersed wounds are associated with tissue necrosis, infection, prolonged healing period, and high mortality because of high salinity, hyperosmosis, and the presence of various pathogenic bacteria in seawater. However, current wound dressings can hardly achieve strong and stable wet adhesion and antibacterial properties, thus limiting their application to seawater-immersed wounds. Here a multifunctional hydrogel (OD/EPL@Fe) comprising catechol-modified oxidized hyaluronic acid (OD), ε-poly-L-lysine (EPL), and Fe3+ was prepared primarily through Schiff-base reaction, metal chelation, cation-π, and electrostatic interaction. The hydrogel with high wet adhesion (about 78 kPa) was achieved by combining the mussel-inspired strategy, dehydration effect, and cohesion enhancement, which is higher than that of commercial fibrin glues and cyanoacrylate glues. Meanwhile, the hydrogel can eliminate Marine bacteria (V. vulnificus and P. aeruginosa) and inhibit their biofilm formation. In addition, the hydrogel demonstrated injectability, self-healing, reactive oxygen species scavenging activity, photothermal effect, seawater isolation, on-demand removal, and hemostatic properties. In vivo results showed that the hydrogel had good adhesion to dynamic wounds in a rat neck full-thickness skin wound model. In particular, the hydrogel exhibited antibacterial, anti-inflammatory, and antioxidant properties in a rat seawater-immersed infected wound model and accelerated the reconstruction of skin structure and functions. The results demonstrated that the OD/EPL@Fe would be a potential wound dressing for seawater-immersed wound healing. STATEMENT OF SIGNIFICANCE: A multifunctional OD/EPL@Fe hydrogel has been prepared for the treatment of seawater-immersed wounds. The hydrogel with high wet adhesion was achieved by combining the mussel-inspired strategy, dehydration effect, and cohesion enhancement. The results revealed that the wet adhesion value of hydrogel was about eight times greater than commercial fibrin glues and 1.5 times greater than commercial cyanoacrylate glues. The hydrogel can be easily removed after being sprayed with deferoxamine mesylate. Notably, the inherent antimicrobial material of the hydrogel combined with the photothermal effect can eliminate marine bacteria and inhibit their biofilm formation. Moreover, the hydrogel can accelerate the healing of seawater-immersed infected wound on mice.

Tumor Acidic Microenvironment-Responsive Promodulator Iron Oxide Nanoparticles for Photothermal-Enhanced Chemodynamic Immunotherapy of Cancer.

Cancer nanomedicine combined with immunotherapy has emerged as a promising strategy for the treatment of cancer. However, precise regulation of the activation of antitumor immunity in targeting tissues for safe and effective cancer immunotherapy remains challenging. Herein, we report a tumor acidic microenvironment-responsive promodulator iron oxide nanoparticle (termed as FGR) with pH-activated action for photothermal-enhanced chemodynamic immunotherapy of cancer. FGR is formed via surface-modifying iron oxide nanoparticles with a dextran-conjugated Toll-like receptor agonist (R848) containing an acid-labile bond. In an acidic tumor microenvironment, the acid-responsive bonds are hydrolyzed to trigger the specific release of R848 to promote the maturation of dendritic cells. In addition, iron oxide nanoparticles within FGR exert photothermal and chemodynamic effects under near-infrared laser irradiation to directly kill tumor cells and induce immunogenic cell death. The synergistic effect of the released immunogenic factors and the acid-activated TLR7/8 pathway stimulates the formation of strong antitumor immunity, resulting in increased infiltration of cytotoxic CD8+ T cells into tumor tissues. As a result, FGR achieves acid-responsive on-demand release and activation of modulators in tumor sites and mediates photothermal-enhanced chemodynamic immunotherapy to inhibit the growth and metastasis of melanoma. Therefore, this work proposes a general strategy for designing prodrug nanomedicines to accurately regulate cancer immunotherapy.

miR-21-5p prevents doxorubicin-induced cardiomyopathy by downregulating BTG2.

Cardiomyocyte apoptosis has been characterized as one of the major mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy. MicroRNA-21-5p (miR-21-5p) was reported to mitigate ischemia-induced cardiomyocyte apoptosis and cardiac injury. However, to our knowledge, the functional role of miR-21-5p in DOX-induced cardiomyopathy is unclear. In this study, we explored the role of miR-21-5p in DOX-induced cardiac injury. The expression level of miR-21-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Dual luciferase reporter assay was used to verify the potential target gene of miR-21-5p. The apoptosis rate of NRCMs was detected by TUNEL staining assay. Western blot analysis was used to detect the protein expression levels of Bax, Bcl-2, Caspase3, cleaved-Caspase3 and BTG2. For animal studies, mice were injected with AAV9-miR-21-5p or AAV9-Empty viruses, and treated with DOX at a dose of 5 mg/kg per week through intraperitoneally administration. After 4 weeks of DOX treatment, mice were subjected to echocardiography to measure the left ventricular ejection fraction (EF) and fractional shortening (FS). Results showed that miR-21-5p was upregulated in both DOX-treated primary cardiomyocytes and mouse heart tissues. Interestingly, enhanced miR-21-5p expression inhibited DOX-induced cardiomyocyte apoptosis and oxidative stress, while decreased miR-21-5p expression promoted cardiomyocyte apoptosis and oxidative stress. Furthermore, cardiac overexpression of miR-21-5p protected against DOX-induced cardiac injury. The mechanistic study indicated that BTG2 was a target gene of miR-21-5p. The anti-apoptotic effect of miR-21-5p could be inhibited by BTG2 overexpression. Conversely, inhibition of BTG2 rescued the pro-apoptotic effect of miR-21-5p inhibitor. Taken together, our study showed that miR-21-5p could prevent DOX-induced cardiomyopathy by downregulating BTG2.

A multifunctional hydrogel loaded with two nanoagents improves the pathological microenvironment associated with radiation combined with skin wounds.

Persistent oxidative stress and recurring waves of inflammation with excessive reactive oxygen species (ROS) and free radical accumulation could be generated by radiation. Exposure to radiation in combination with physical injuries such as wound trauma would produce a more harmful set of medical complications, which was known as radiation combined with skin wounds (RCSWs). However, little attention has been given to RCSW research despite the unsatisfactory therapeutic outcomes. In this study, a dual-nanoagent-loaded multifunctional hydrogel was fabricated to ameliorate the pathological microenvironment associated with RCSWs. The injectable, adhesive, and self-healing hydrogel was prepared by crosslinking carbohydrazide-modified gelatin (Gel-CDH) and oxidized hyaluronic acid (OHA) through the Schiff-base reaction under mild condition. Polydopamine nanoparticles (PDA-NPs) and mesenchymal stem cell-secreted small extracellular vesicles (MSC-sEV) were loaded to relieve radiation-produced tissue inflammation and oxidation impairment and enhance cell vitality and angiogenesis individually or jointly. The proposed PDA-NPs@MSC-sEV hydrogel enhanced cell vitality, as shown by cell proliferation, migration, colony formation, and cell cycle and apoptosis assays in vitro, and promoted reepithelization by attenuating microenvironment pathology in vivo. Notably, a gene set enrichment analysis of proteomic data revealed significant enrichment with adipogenic and hypoxic pathways, which play prominent roles in wound repair. Specifically, target genes were predicted based on differential transcription factor expression. The results suggested that MSC-sEV- and PDA-NP-loaded multifunctional hydrogels may be promising nanotherapies for RCSWs. STATEMENT OF SIGNIFICANCE: The small extracellular vesicle (sEV) has distinct advantages compared with MSCs, and polydopamine nanoparticles (PDA-NPs), known as the biological materials with good cell affinity and histocompatibility which have been reported to scavenge ROS free radicals. In this study, an adhesive, injectable, self-healing, antibacterial, ROS scavenging and amelioration of the radiation related microenvironment hydrogel encapsulating nanoscale particles of MSC-sEV and PDA-NPs (PDA-NPs@MSC-sEV hydrogel) was synthesized for promoting radiation combined with skin wounds (RCSWs). GSEA analysis profiled by proteomics data revealed significant enrichments in the regulations of adipogenic and hypoxic pathways with this multi-functional hydrogel. This is the first report of combining this two promising nanoscale agents for the special skin wounds associated with radiation.

Diagnosis of acute myocardial infarction using a combination of circulating circular RNA cZNF292 and clinical information based on machine learning.

Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof-of-concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia-induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non-AMI patients. Based on feature selection by using lasso with 10-fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM + cZNF292 can separate AMI and non-AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non-ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti-apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model "CM + cZNF292."

A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy.

Immunotherapy has been used for cancer treatment, while it faces the common dilemmas of low therapeutic efficacy and serious immunotoxicity. In this study, we report the construction of a tumor microenvironment and near-infrared (NIR) light dual-responsive prodrug hydrogel for cancer synergistic immunotherapy in a more effective and safe manner. Such prodrug hydrogels were in-situ formed via calcium-induced gelation of alginate solution containing protoporphyrin IX (PpIX)-modified iron oxide (Fe3O4) nanoparticles and programmed death ligand 1 antibody (aPD-L1) prodrug nanoparticles crosslinked by reactive oxygen species (ROS)-responsive linkers. PpIX served as a photosensitizer to produce singlet oxygen (1O2) under NIR laser irradiation for photodynamic therapy (PDT), and Fe3O4 nanoparticles mediated chemodynamic therapy (CDT) to generate hydroxyl radical (·OH) via Fenton reaction in the tumor microenvironment. In view of the cumulative actions of PDT and CDT, amplified ROS was generated to not only induce immunogenic cell death (ICD), but also destroy ROS-responsive linkers to achieve on-demand release of aPD-L1 from prodrug nanoparticles. Boosted antitumor immunity was elicited in tumor-bearing mice due to the aPD-L1-mediated immune checkpoint blocking. As a result, the prodrug hydrogel-based synergistic immunotherapy could almost treat bilateral tumors and prevent lung and liver metastasis using 4T1 tumor mouse models. This study thus offers a dual-responsive prodrug hydrogel platform for precision cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Via calcium-induced gelation of alginate, we constructed a prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy. Such hydrogels can achieve on-demand release of aPD-L1 upon photoactivation in the tumor microenvironment. Through mediating photodynamic and chemodynamic therapy, the prodrug hydrogels can induce enhanced immunogenic cell death and synergistically improve the efficacy of aPD-L1-mediated immune checkpoint blocking. The prodrug hydrogel-based synergistic therapy almost deracinates the primary and distant tumors, and prevents lung and liver metastasis in tumor mouse models.

Biomimetic Asymmetric Composite Dressing by Electrospinning with Aligned Nanofibrous and Micropatterned Structures for Severe Burn Wound Healing.

The surface structure and topography of biomaterials play a crucial role in directing cell behaviors and fates. Meanwhile, asymmetric dressings that mimic the natural skin structure have been identified as an effective strategy for enhancing wound healing. Inspired by the skin structure and the superhydrophobic structure of the lotus leaf, an asymmetric composite dressing was obtained by constructing an asymmetric structure and wettability surface modification on both sides of the sponge based on electrospinning. Among them, the collagen and quaternized chitosan sponge was fabricated by freeze-drying, followed by an aligned poly(ε-caprolactone) (PCL)/gelatin nanofiber hydrophilic inner layer and hierarchical micronanostructure PCL/polystyrene microsphere highly hydrophobic outer layer constructed on each side of the sponge. The proposed asymmetric composite dressing combines topological morphology with the material's properties to effectively prevent bacterial colonization/infection and promote wound healing by directing cellular behavior. In vitro experimental results confirmed that the aligned nanofiber inner layer effectively promotes cell adhesion, proliferation, directed cell growth, and migration. Meanwhile, the sponge has good water absorption and antibacterial properties, while the biomimetic hydrophobic outer layer exhibits strong mechanical properties and resistance to bacterial adhesion. In vivo results showed that the composite dressing can reduce inflammatory response, prevent infection, accelerate angiogenesis and epithelial regeneration, and significantly accelerate the healing of severe burns. Thus, the proposed bionic asymmetric dressing is expected to be a promising candidate for severe burn wound healing.

Simultaneous recovery of ammonium and total phosphorus from toilet tail water by modified palygorskite-bentonite clay.

Suitable treatment of toilet sewage is a worldwide challenge. The anaerobic baffled reactor (ABR)-microbial fuel cell (MFC)-microbial electrolysis cell (MEC) (AMM) coupling treatment system has been constructed achieving effective removal of carbon, nitrogen, and phosphorus from toilet sewage and resource recovery; however, ammonium (NH4 + -N) and total phosphorus (TP) accumulation in tail water is a found problem of the system. In this study, acid-modified and alkali-heat modified palygorskite-bentonite (Pal-Ben) were used to recover NH4 + -N and TP from the AMM toilet tail water simultaneously. The higher adsorption capacity of the modified clay is attributed to the changes of surface structure of the material. The modified clay Pal-Ben (mass ratio 1:3) activated with alkali performed the highest NH4 + -N and TP recovery rates of 83.6% and 85.5%, respectively. The adsorption of NH4 + -N was more in line with the pseudo-second-order kinetic model and confirmed to be a chemical adsorption process, while the adsorption of TP was more in line with the pseudo-first-order kinetics and a physical adsorption process; the adsorption capacity of NH4 + -N accelerated with decrease of TP removal when pH increased. This study developed a low cost and high capacity of alkaline thermally modified clay removing/recovering NH4 + -N and TP from toilet tail water simultaneously. PRACTITIONER POINTS: A cheap composite clay was developed to recover nitrogen and phosphorus from toilet tail water simultaneously. The low costs and high capacity of alkaline thermally modified clay make it stand out in NH4 + -N and TP removal of toilet tail water. The process mechanism of simultaneous nitrogen and phosphorus recovery was clarified with characterization and kinetic model fitting. The used clay loaded with nutrients could be applied as a slow-release compound fertilizer for soil improvement.

Configuration and rapid start-up of a novel combined microbial electrolytic process treating fecal sewage.

Most of the developing countries are in need of sanitary toilets due to insufficient supporting facilities and proven technology mainly on disposal of fecal sewage. A microbial fuel cell (MFC)-microbial electrolytic cell (MEC) coupling with an anaerobic baffle reactor (ABR) was used to realize simultaneous removal of nitrogen and carbon in fecal sewage and complete energy recycling. Configuration and rapid start-up of the ABR-MFC-MEC process treating fecal sewage was systematically studied. Results showed that the application of an external voltage of 0.5 V can shorten the start-up time and improve hydrogen production rate to 3.42 × 10-3 m3-H2/m3/d in the MEC unit, where the double-chamber MFC can drive MEC completing the synchronous coupling start-up. In the single and double chamber systems, bio-electrochemical processes both enhanced shock resistance capacity of the whole ABR-MFC-MEC process during coupled operation, with chemical oxygen demand (COD) removal rates of 99.2% and 98.9% for the single and double chamber systems respectively. Based on results of biological analysis, the coupled system has a distinct selective effect on microbial population and each unit has high microbial diversity to enhance the stability and resistance of the whole system for treatment of feces and urine.

Circulating microRNAs in Response to Exercise Training in Healthy Adults.

Circulating microRNAs (miRNAs, miRs) have great potential as cardiac biomarkers and they are also being explored for their roles in intercellular communication and gene expression regulation. The analysis of circulating miRNAs in response to exercise would provide a deeper understanding of the molecular response to physical activity and valuable information for clinical practice. Here, eight male college students were recruited to participate in cardiopulmonary exercise testing (CPET) and 1 h acute exercise training (AET). Blood samples were collected and serum miRNAs involved in angiogenesis, inflammation and enriched in muscle and/or cardiac tissues were analyzed before and after cardiopulmonary exercise and acute exercise. The miRNAs we detected were miR-1, miR-20a, miR-21, miR-126, miR-133a, miR-133b, miR-146, miR155, miR-208a, miR-208b, miR-210, miR-221, miR-222, miR-328, miR-378, miR-499, and miR-940. We found that serum miR-20a was decreased significantly after CPET and serum miR-21 was increased after AET. In addition, no robust correlation was identified between the changes of these miRNAs and makers of cardiac function and exercise capacity, which indicates a distinct adaptation of these miRNAs to exercise. Future studies are highly needed to define the potential use of these circulating miRNAs as useful biomarkers of exercise training, and disclose the biological function of circulating miRNAs as physiological mediators of exercise-induced cardiovascular adaptation.

MicroRNAs in heart and circulation during physical exercise.

Exercise training is beneficial to the cardiovascular system. MicroRNAs (miRNAs, miRs) are a class of conserved non-coding RNAs and play a wide-ranging role in the regulation of eukaryotic gene expression. Exercise training alters the expression levels of large amounts of miRNAs in the heart. In addition, circulating miRNAs appear to be regulated by exercise training. In this review, we will summarize recent advances in the regulation of miRNAs during physical exercise intervention in various cardiovascular diseases, including pathologic cardiac hypertrophy, myocardial fibrosis, ischemia-reperfusion injury, myocardial infarction, and heart failure. The regulatory role of circulating miRNAs after exercise training was also reviewed. In conclusion, miRNAs might be a valuable target for treatment of cardiovascular diseases and have great potential as biomarkers for assessment of physical performance.