Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy.

Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d(Jinx) (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT→WT) and WT mice that received Jinx bone marrow (Jinx→WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx→WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.

Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia.

OBJECTIVE: The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. METHODS AND RESULTS: We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. CONCLUSIONS: Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.

A counter-gravity casting system for in situ high-speed synchrotron x-ray imaging characterization.

Counter-gravity casting (CGC) aims to eliminate turbulent melt flow and defect formation during filling and subsequent solidification by pushing high-temperature melt into the mold cavity against gravity with regulated pressure. However, limited by the opaqueness of molten metals and the complexity of the CGC apparatus, it is extremely difficult to directly quantify the high-velocity mold filling and pressurized solidification in real-time. Here, we report the design and characterization of a CGC system capable of in situ monitoring of mold filling and subsequent solidification processes in the synchrotron beamlines by deploying a high-energy, high-speed synchrotron x-ray imaging technique. The high-velocity melt flow and dendrite growth during pressurized solidification have been quantified for systematical process parameter analysis by investigating time-resolved x-ray images of an exemplary Al-Cu alloy. The high-speed imaging results demonstrate that the in situ CGC system provides a useful way to better understand the fundamentals of mold filling, pressurized solidification, and experimental inputs for high-fidelity modeling in scientific and industrial applications.

Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator. Concentrations of the major LPA species in mouse plasma decreased uniformly following administration of a potent selective inhibitor of the LPA-generating lysophospholipase D autotaxin, identifying an active mechanism for removal of LPA from the circulation. LPA, akylglycerol phosphate (AGP), sphingosine 1-phosphate (S1P), and a variety of structural mimetics of these lipids, including phosphatase-resistant phosphonate analogs of LPA, were rapidly eliminated (t1/2 < 30 s) from the circulation of mice following intravenous administration of a single bolus dose without significant metabolism in situ in the blood. These lipids accumulated in the liver. Elimination of intravenously administered LPA was blunted by ligation of the hepatic circulation, and ∼90% of LPA administered through the portal vein was accumulated by the isolated perfused mouse liver at first pass. At early times following intravenous administration, more LPA was associated with a nonparenchymal liver cell fraction than with hepatocytes. Primary cultures of nonparenchymal liver cells rapidly assimilated exogenously provided LPA. Our results identify hepatic uptake as an important determinant of the bioavailability of LPA and bioactive lysophospholipid mimetics and suggest a mechanism to explain changes in circulating LPA levels that have been associated with liver dysfunction in humans.

Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation.

Nitric oxide (NO) stimulates cGMP synthesis by activating its intracellular receptor, soluble guanylyl cyclase (sGC). It is a currently prevailing concept that No and cGMP inhibits platelet function. However, the data supporting the inhibitory role of NO/sGC/cGMP in platelets have been obtained either in vitro or using whole body gene deletion that affects vessel wall function. Here we have generated mice with sGC gene deleted only in megakaryocytes and platelets. Using the megakaryocyte- and platelet-specific sGC-deficient mice, we identify a stimulatory role of sGC in platelet activation and in thrombosis in vivo. Deletion of sGC in platelets abolished cGMP production induced by either NO donors or platelet agonists, caused a marked defect in aggregation and attenuated secretion in response to low doses of collagen or thrombin. Importantly, megakaryocyte- and platelet-specific sGC deficient mice showed prolonged tail-bleeding times and impaired FeCl3-induced carotid artery thrombosis in vivo. Interestingly, the inhibitory effect of the NO donor SNP on platelet activation was sGC-dependent only at micromolar concentrations, but sGC-independent at millimolar concentrations. Together, our data demonstrate important roles of sGC in stimulating platelet activation and in vivo thrombosis and hemostasis, and sGC-dependent and -independent inhibition of platelets by NO donors.

Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.

OBJECTIVE: Lysophosphatidic acid (LPA) is a bioactive lipid molecule produced by the plasma lysophospholipase D enzyme autotaxin that is present at ≥100 nmol/L in plasma. Local administration of LPA promotes systemic arterial remodeling in rodents. To determine whether LPA contributes to remodeling of the pulmonary vasculature, we examined responses in mice with alterations in LPA signaling and metabolism. METHODS AND RESULTS: Enpp2(+/-) mice, which are heterozygous for the autotaxin-encoding gene and which have reduced expression of autotaxin/lysophospholipase D and approximately half normal plasma LPA, were hyperresponsive to hypoxia-induced vasoconstriction and remodeling, as evidenced by the development of higher right ventricular (RV) systolic pressure, greater decline in peak flow velocity across the pulmonary valve, and a higher percentage of muscularized arterioles. Mice lacking LPA(1) and LPA(2), 2 LPA receptors abundantly expressed in the vasculature, also had enhanced hypoxia-induced pulmonary remodeling. With age, Lpar1(-/-)2(-/-) mice spontaneously developed elevated RV systolic pressure and RV hypertrophy that was not observed in Lpar1(-/-) mice or Lpar2(-/-) mice. Expression of endothelin-1, a potent vasoconstrictor, was elevated in lungs of Lpar1(-/-)2(-/-) mice, and expression of endothelin(B) receptor, which promotes vasodilation and clears endothelin, was reduced in Enpp2(+/-) and Lpar1(-/-)2(-/-) mice. CONCLUSIONS: Our findings indicate that LPA may negatively regulate pulmonary vascular pressure through LPA(1) and LPA(2) receptors and that in the absence of LPA signaling, upregulation in the endothelin system favors remodeling.

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation.

Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC(50) approximately 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.

Spontaneous and Selective Potassium Transport through a Suspended Tailor-Cut Ti3C2Tx MXene Film.

Biological ion pumps selectively transport target ions against the concentration gradient, a process that is crucial to maintaining the out-of-equilibrium states of cells. Building an ion pump with ion selectivity has been challenging. Here we show that a Ti3C2Tx MXene film suspended in air with a trapezoidal shape spontaneously pumps K+ ions from the base end to the tip end and exhibits a K+/Na+ selectivity of 4. Such a phenomenon is attributed to a range of properties of MXene. Thanks to the high stability of MXene in water and the dynamic equilibrium between evaporation and swelling, the film keeps a narrow interlayer spacing of ∼0.3 nm when its two ends are connected to reservoirs. Because of the polar electrical structure and hydrophilicity of the MXene nanosheet, K+ ions experience a low energy barrier of ∼4.6 kBT when entering these narrow interlayer spacings. Through quantitative simulations and consistent experimental results, we further show that the narrow spacings exhibit a higher energy barrier to Na+, resulting in K+/Na+ selectivity. Finally, we show that the spontaneous ion transport is driven by the asymmetric evaporation of the interlayer water across the film, a mechanism that is similar to pressure driven streaming current. This work shows how ion transport properties can be facilely manipulated by tuning the macroscopic shape of nanofluidic materials, which may attract interest in the interface of kirigami technologies and nanofluidics and show potential in energy and separation applications.

Challenges and Strategies of Low-Cost Aluminum Anodes for High-Performance Al-Based Batteries.

The ever-growing market of electric vehicles and the upcoming grid-scale storage systems have stimulated the fast growth of renewable energy storage technologies. Aluminum-based batteries are considered one of the most promising alternatives to complement or possibly replace the current lithium-ion batteries owing to their high specific capacity, good safety, low cost, light weight, and abundant reserves of Al. However, the anode problems in primary and secondary Al batteries, such as, self-corrosion, passive film, and volume expansion, severely limit the batteries' practical performance, thus hindering their commercialization. Herein, an overview of the currently emerged Al-based batteries is provided, that primarily focus on the recent research progress for Al anodes in both primary and rechargeable systems. The anode reaction mechanisms and problems in various Al-based batteries are discussed, and various strategies to overcome the challenges of Al anodes, including surface oxidation, self-corrosion, volume expansion, and dendrite growth, are systematically summarized. Finally, future research perspectives toward advanced Al batteries with higher performance and better safety are presented.

Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses but not blood pressure.

Phenotypic modulation of vascular smooth muscle cells (SMCs) is essential for the development of intimal hyperplasia. Lysophosphatidic acid (LPA) is a serum component that can promote phenotypic modulation of cultured SMCs, but an endogenous role for this bioactive lipid as a regulator of SMC function in vivo has not been established. Ligation injury of the carotid artery in mice increased levels in the vessel of both autotaxin, the lysophospholipase D enzyme responsible for generation of extracellular LPA, and 2 LPA responsive G protein-coupled receptors 1 (LPA1) and 2 (LPA2). LPA1(-/-)2(-/-) mice were partially protected from the development of injury-induced neointimal hyperplasia, whereas LPA1(-/-) mice developed larger neointimal lesions after injury. Growth in serum, LPA-induced extracellular signal-regulated protein kinase activation, and migration to LPA and serum were all attenuated in SMCs isolated from LPA1(-/-)2(-/-) mice. In contrast, LPA1(-/-) SMCs exhibited enhanced migration resulting from an upregulation of LPA3. However, despite their involvement in intimal hyperplasia, neither LPA1 nor LPA2 was required for dedifferentiation of SMCs following vascular injury or dedifferentiation of isolated SMCs in response to LPA or serum in vitro. Similarly, neither LPA1 nor LPA2 was required for LPA to elicit a transient increase in blood pressure following intravenous administration of LPA to mice. These results identify a role for LPA1 and LPA2 in regulating SMC migratory responses in the context of vascular injury but suggest that additional LPA receptor subtypes are required for other LPA-mediated effects in the vasculature.

New Constitutive Model for the Size Effect on Flow Stress Based on the Energy Conservation Law.

In this study, a new model involving energy is established to characterize the size effect on flow stress. The new model treats the experimental machine and the specimen as an isolated system, and this isolated system satisfies the Energy Conservation Law. The total work performed on the specimen by the experimental machine is nearly equal to the energy consumed by the specimen plastic deformation and the energy consumed by friction (which can be ignored when working without friction). The new model predicts the energy consumption of the specimen deformation by quantifying the total energy input to the specimen by the experimental machine and then obtaining the relevant parameters of the constitutive model. Through uniaxial tensile tests of pure nickel thin sheets with various thickness/average grain sizes (t/d), the new model was used to optimize the parameters of the existing constitutive model that predicts the flow stress of specimens with different t/d. The prediction accuracy of the optimized constitutive model is improved, especially for specimens with a t/d < 1. The new model is established from the perspective of energy input to avoid the analysis of the material deformation mechanism and improve the prediction accuracy.

Microstructure and properties of TC4/TNTZO multi-layered composite by direct laser deposition.

In this work, TC4/TNTZO multi-layered composite as well as TNTZO and TC4 alloys were prepared by direct laser deposition (DLD) to investigate the microstructure, mechanical properties and in vitro bioactivity. The microstructure characterization shows that the multi-layered material is free of cracks and intermetallics while the interface is metallurgically bonded. The fine microstructure was observed in TC4 layer of the TC4/TNTZO multi-layered material, and a large amount of α' martensite exists in the transition zone. Different from the single ß phase cellular arrays in the DLD-ed TNTZO alloy, α″ martensite with high volume content formed at the cellular grain boundary in TNTZO zone of DLD-ed TC4/TNTZO. The elastic modulus of the DLD-ed TC4/TNTZO is 64 GPa, decreased about 45% compared to the DLD-ed TC4. The tensile yield strength and elongation along the printing direction are up to 789 MPa and 7%, which are 12% higher than the tensile yield strength of DLD-ed TNTZO and 61% higher than the elongation of DLD-ed TC4 respectively. Moreover, the DLD-ed TC4/TNTZO shows good in vitro bioactivity. The TC4/TNTZO multi-layered composite fabricated by DLD can be regarded as a potential candidate to integrate the advantages of the two Ti-base alloys for application in the biomedical field.

Design of high-ductile medium entropy alloys for dental implants.

Developing new materials with high strength and ductility, low modulus and high biocompatibility is a continuing demand in the field of surgical implants. Inspired by the high-entropy design philosophy, two medium entropy alloys (MEAs), i.e. equiatomic TiZrHf and equi-weight Ti40Zr20Hf10Nb20Ta10 were designed and their mechanical properties and biocompatibility were assessed. Both the single-phase hexagonal close-packed (HCP) structured TiZrHf alloy and the single-phase body-centered cubic (BCC) structured Ti40Zr20Hf10Nb20Ta10 alloy show high strength-ductility combinations close to commercial Ti-6Al-4V wrought alloy and remarkably lower young's modulus than commercial pure titanium (CP-Ti) and Ti-6Al-4V. From the aspects of adhesion, proliferation, toxicity and related gene expression of human gingival fibroblasts (HGFs), the Ti40Zr20Hf10Nb20Ta10 alloy exhibits distinctively better biocompatibility than that of CP-Ti while the TiZrHf shows only slightly better biocompatibility as compared with CP-Ti. These results indicate that these two ductile MEAs are potential candidates for dental application.

Reversible Photodriven Droplet Motion on Ti3C2 MXene Film for Diverse Liquids.

The manipulation of liquid droplets on a specific surface with reversible wettability is of great importance for various applications from science to industry. Herein, the concept of a smart, flexible photodriven droplet motion (PDM) device with programmable wettability is designed using the 2D material of MXene film. Because of the MXene photothermal property, the Vaseline layer in the device is in transition between solid and liquid states under the heat transformation due to light illumination, thus attractively producing a reversible wettability for liquid motion with respect to sliding and pinning. Multifarious pathways for liquid motion could be designed through the flexibility of light illumination, which is a revolutionary enhancement in diverse liquid motion to form the desired pathways. In addition, we demonstrated liquid motion under illumination of the back face, which has a profound influence on applications, such as microfluidic systems, microengines, and liquid manipulation.

Parent-of-origin effects on cardiac response to pressure overload in mice.

Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular mortality and is commonly caused by hypertension. In rodents, transverse aortic constriction (TAC) is a model regularly employed in mechanistic studies of the response of the LV to pressure overload. We previously reported that inbred strains of male mice manifest different cardiac responses to TAC, with C57BL/6J (B6) developing LV dilatation and impaired contractility and 129S1/SvImJ (129) males displaying concentric LVH. In the present study, we investigated sex and parent-of-origin effects on the response to TAC by comparing cardiac function, organ weights, expression of cardiac hypertrophy markers, and histology in female B6 and female 129 mice and in F1 progeny of reciprocal crosses between B6 and 129 mice (B6129F1 and 129B6F1). Five weeks after TAC, heart weight increased to the greatest extent in 129B6F1 mice and the least extent in 129 and B6129F1 mice. Female 129B6F1 and B6 mice were relatively protected from the increase in heart weight that occurs in their male counterparts with pressure overload. The response to TAC in 129 consomic mice bearing the B6 Y chromosome resembled that of 129 rather than 129B6F1 mice, indicating that the B6 Y chromosome does not account for the differences in the reciprocal cross. Our results suggest that susceptibility to LVH is more complex than simple Mendelian inheritance and that parental origin effects strongly impact the LV response to TAC in these commonly used inbred strains.

Effects of Withdrawal Rate on the Microstructure of Directionally Solidified GH4720Li Superalloys.

Increasing the ingot size of GH4720Li superalloys makes it difficult to control their microstructure, and the withdrawal rate is an important factor in controlling and refining the microstructure of GH4720Li superalloys. In this study, GH4720Li superalloy samples were prepared via Bridgman-type directional solidification with different withdrawal rates. The morphology and average size of the dendrites in the stable growth zone during directional solidification in each sample, morphology and average size of the γ' phases, and microsegregation of each alloying element were analyzed using optical microscopy, Photoshop, Image Pro Plus, field emission scanning electron microscopy, and electron probe microanalysis. Increasing the withdrawal rate significantly helped in refining the superalloy microstructure; the average secondary dendrite arm spacing decreased from 133 to 79 µm, whereas the average sizes of the γ' phases in the dendrite arms and the interdendritic regions decreased from 1.02 and 2.15 µm to 0.69 and 1.26 µm, respectively. Moreover, the γ' phase distribution became more uniform. The microsegregation of Al, Ti, Cr, and Co decreased with the increase in the withdrawal rate; the segregation coefficients of Al, Cr, and Co approached 1 at higher withdrawal rates, whereas that of Ti remained above 2.2 at all the withdrawal rates.

Effects of Heat-Treatment Temperature on the Microstructure and Mechanical Properties of Steel by MgO Nanoparticle Additions.

The characteristics and formation mechanisms of intragranular acicular ferrite (IAF) in steel with MgO nanoparticle additions were systematically investigated for different isothermal heat-treatment temperatures, and its influence on mechanical properties was also clarified. The results indicate that the inclusions were finely dispersed and refined after adding MgO nanoparticles. In addition, with decreasing heat-treatment temperature, the microstructure changed from grain boundary ferrite (GBF) and polygonal ferrite (PF) to intragranular acicular ferrite. Moreover, the steel with MgO additions had excellent mechanical properties in the temperature range of 973 to 823 K and an average Charpy absorbed energies value of around 174 J at 873 K due to the significant refinement of the microstructure and nucleation of intragranular acicular ferrite.

Effects of Different Melting Technologies on the Purity of Superalloy GH4738.

The choice of melting technique is crucial for controlling the purity of a superalloy, which is especially important because purity has come to limit progress in the superalloy field. In this study, double- and triple-melting techniques were used to refine the GH4738 superalloy. Elemental analyses, inductively coupled plasma-atomic emission spectroscopy, X-ray diffraction analysis, scanning electron microscopy with energy-dispersive spectroscopy, high-temperature cupping machine, high-temperature fatigue testing machine, and Image-Pro Plus software were used to analyze and compare the contents of specific elements, the types and sizes of inclusions, the mechanical properties, and the probabilities of white spot formation using the two melting techniques. The effects of the different melting processes on the purity of the superalloy were systematically studied. In terms of controlling the presence of impurities, the triple-melting process resulted in lower levels of harmful N, S, and O impurities in the superalloy, the triple-melted superalloy also contained fewer types of inclusion of smaller sizes and in smaller amounts than the double-melted alloy. Triple melting also promotes tensile strength and fatigue life, and minimizes the probability of forming defects in the superalloy.

Effect of Mg on the Microstructure and Corrosion Resistance of the Continuously Hot-Dip Galvanizing Zn-Mg Coating.

The microstructure of continuously hot-dip galvanizing Zn-Mg coating was investigated in order to obtain the mechanism of the effects of Mg on the corrosion resistance. In this paper, the vertical section of the Zn-0.20 wt % Al-Mg ternary phase diagram near the Al-low corner was calculated. The results indicates that the phase composition of the Zn-0.20 wt % Al-Mg ternary phase diagram near the Al-low corner is the same as Zn-Mg binary phase diagram, suggesting Al in the Zn-Mg (ZM) coatings mainly concentrates on the interfacial layer between the coating and steel substrate. The microstructure of continuously hot-dip galvanizing ZM coatings with 0.20 wt % Al containing 1.0-3.0 wt % Mg was investigated using tunneling electron microscopy (TEM). The morphology of Zn in the coating changes from bulk to strip and finally to mesh-like, and the MgZn2 changes from rod-like to mesh-like with the Mg content increasing. Al in the ZM coatings mainly segregates at the Fe2Al5 inhibition layer and the Mg added to the Zn bath makes this inhibition layer thinner and uneven. Compared to GI coating, the time of the first red rust appears increases by more than two-fold and expansion rate of red rust reduces by more than four-fold in terms of salt spray experiment. The ZM coating containing 2.0 wt % Mg has the best corrosion resistance. The enhanced corrosion resistance of ZM coatings mainly depends on different corrosion products.

Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice.

INTRODUCTION: The multifunctional serine protease thrombin exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling. This study was designed to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure. MATERIAL AND METHODS: Transverse aortic constriction (TAC) surgery was performed on C57Bl/6J male mice to elicit cardiac hypertrophy. TAC, or sham, mice were randomly assigned to receive chow supplemented with the oral anticoagulant, dabigatran etexilate, or placebo. RESULTS: Dabigatran did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia length, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran reduced perivascular fibrosis by 25%, interstitial fibrosis by 54%, and the expression of myocardial fibrosis markers collagen I & III, MMP9, SMA, and PAR-1. These changes were associated with significant improvement in both coronary flow reserve and global left ventricular function. In cultured cardiac fibroblasts, dabigatran decreased thrombin and PAR-1-mediated collagen deposition by 30% and 37%, respectively. CONCLUSIONS: Dabigatran attenuates cardiac fibrosis in the setting of pressure overload and improves coronary flow reserve and global cardiac function possibly by inhibiting thrombin activity and down-regulating PAR-1 expression in the absence of an effect on cardiomyocyte hypertrophy.