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Deep‐sea exploration remains a challenging task as the extreme hydrostatic pressure environment, darkness, and suspended sediment launch severely hinder the capability of deep‐sea vehicles. As a complement to underwater camera, tactile perception becomes especially important in situations where machine vision is limited. However, tactile sensors utilized in deep sea, which should be able to detect pressure changes of only hundreds of pascals under high hydrostatic pressure, are still lacking. To tackle the challenge imposed by hydrostatic pressure, a simulated deep‐sea environment flexible sensor (SDEFS) is proposed, consisting of a force sensor array and a bending sensor based on hydrogels for tactile sensing in 50 MPa hydrostatic pressure environments. The force sensor is unaffected by the hydrostatic pressure and achieves high sensitivity of 82.62 N−1 under 100 MPa hydrostatic pressure. The SDEFS is utilized to classify objects based on the difference in hardness. It can accurately classify seven objects on the ground, and three objects in an underwater environment with hydrostatic pressure of 50 MPa, with total recognition accuracies of 98.3% and 96%, respectively. With high force measurement sensitivity and accurate recognition ability under water, the SDEFS is expected to provide very valuable haptic sensing and feedback in deep‐sea exploration.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94 μg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1 K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1 WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3β pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Qile, Muge, Qiying Xu, Yi Ye, Huifang Liu, Drolma Gomchok, Juanli Liu, Tana Wuren, and Ri-Li Ge. Erythrocytes display metabolic changes in high-altitude polycythemia. High Alt Med Biol . 24:104-109, 2023. Background: Sphingosine-1-phosphate (S1P) levels are increased after acute exposure to high altitude; however, whether this effect is observed in chronic high-altitude hypoxia is unknown. Methods: We studied erythrocyte S1P levels in 13 subjects with high-altitude polycythemia (HAPC) and 13 control subjects and also used a mouse model of HAPC. HAPC subjects lived in Maduo (4,300 m altitude) for 10 years, whereas control subjects lived permanently in Xining (2,260 m). The mouse model of HAPC was established by stimulating an altitude of 5,000 m in a hypobaric chamber for 30 days. Hematology and S1P, CD73, 2,3-bisphosphoglycerate (2,3-BPG), and reticulocyte levels were measured. Results: The hemoglobin concentration and number of red blood cells were significantly elevated in human and mouse HAPC groups. Blood S1P levels in HAPC subjects and mice were higher than those in control groups ( p  < 0.05 and p  < 0.001, respectively). 2,3-BPG and CD73 levels in HAPC subjects were significantly higher than those in control subjects ( p  < 0.05). No significant changes in reticulocyte levels were observed. Conclusions: The critical altitude-induced metabolic changes such as S1P retained high levels even after prolonged exposure, and it may inspire future research into therapeutic strategies for hypoxia-associated illnesses.

Various studies have described the roles of myeloid-derived suppressor cells (MDSCs) in pathological conditions, but relatively few have described them under normal physiological conditions. Accumulation of MDSCs is important creating an anti-inflammation environment, which is essential for fertilized egg implantation. This study was designed to record the dynamic changes in MDSC-like cells composition during the menstrual period (MP) and ovulation period (OP) in healthy volunteers over the course of a single menstrual cycle to explore the association between MDSCs and the menstrual cycle under normal physiological conditions. The ratio of MDSC-like cells was higher in MP samples, whereas the activity of Arg-1 was higher during the OP window. There was a negative correlation between the ratio of MDSC-like cells and the percentage of lymphocytes and a positive correlation between MDSC-like cells and prostaglandin E2 (PGE2). Furthermore, regular changes in the ratio and function of MDSC-like cells in the peripheral blood were observed during menstruation, all of which corresponded to the cycle stage. During menstruation, MDSCs may promote endometrial repair, whereas they promote pregnancy during the OP. These findings may help to better understand the pathophysiology of pregnancy-related complications and lay a foundation for improving perinatal outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Liu, Qile and Wuren.)

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia-reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Living at high altitudes is extremely challenging as it entails exposure to hypoxia, low temperatures, and high levels of UV radiation. However, the Tibetan population has adapted to such conditions on both a physiological and genetic level over 30,000-40,000 years. It has long been speculated that fetal growth restriction is caused by abnormal placental development. We previously demonstrated that placentas from high-altitude Tibetans were protected from oxidative stress induced by labor compared to those of European descent. However, little is known about how placental mitochondria change during high-altitude adaptation. In this study, we aimed to uncover the mechanism of such adaptation by studying the respiratory function of the placental mitochondria of high-altitude Tibetans, lower-altitude Tibetans, and lower-altitude Chinese Han. We discovered that mitochondrial respiration was greater in high-altitude than in lower-altitude Tibetans in terms of OXPHOS via complexes I and I+II, ETS max capacity, and non-phosphorylating respiration, whereas non-ETS respiration, LEAK/ETS, and OXPHOS via complex IV did not differ. Respiration in lower-altitude Tibetans and Han was similar for all tested respiratory states. Placentas from high-altitude Tibetan women were protected from acute ischemic/hypoxic insult induced by labor, and increased mitochondrial respiration may represent an acute response that induces mitochondrial adaptations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Tenzing, van Patot, Qile, Ge and Wuren.)

Voltage-gated potassium 11.1 (K v 11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated K v 11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal K v 11.1 forward trafficking and thus reduce functional K v 11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a K v 11.1 allosteric modulator/activator, to rescue K v 11.1 trafficking and produce functional K v 11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-K v 11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT K v 11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S-K v 11.1 cells, dofetilide (10 μM) or dofetilide + LUF7244 (10 + 5 μM) also restored K v 11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased I Kv 11.1 despite the presence of dofetilide (1 μM) in WT K v 11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 μM) and dofetilide (1 μM) increased I Kv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues K v 11.1 trafficking and produces functional I Kv11.1 Thus, combined administration of LUF7244 and an I Kv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced K v 11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional K v 11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of K v 11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired K v 11.1 trafficking defects, resulting in functional K v 11.1 current., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

This work presents drug-likeness and the cardiotoxicity profiles of six potent pentamidine analogs 1-6 and three new compounds 7-9 as chemotherapeutics for therapy of Pneumocystis jiroveci pneumonia. A combination of experimental and computational approaches was used in the cardiotoxicity examination. The hERG trafficking and functionality of the hERG currents were tested by western blot analyses, immunofluorescent staining procedures, and patch-clamp electrophysiological assays. Cardiotoxicity combined with blocking the hERG K + channel was predicted, and then simulated by docking to the CSM-TM model 732 protein. Location of pentamidines in the proximity of Leu622, Thr623, Ser649, Tyr652, Ala653, and Phe656, and the high energies of interactions were in accordance with probable blocking of the hERG channel. However, in the biochemical experiments, no significant changes in I hERG densities and a minor effect on hERG maturation were observed. Predicted metabolic transformation of pentamidines with S atoms in the aliphatic linker leads to oxidation of one S atom, but those with the phenyl sulfanilide moiety can be oxidized to chinones. The tested pentamidines characterized by the presence of sulfur atoms or sulfanilide groups, have favorable drug-likeness parameters and are promising lead structures in the development of new potent chemotherapeutics against PJP., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The ubiquitously expressed family of inward rectifier potassium (K IR ) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all K IR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These "mutation clusters" affect trafficking by different mechanisms, including protein stability.

Background and Purpose: K v 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of K v 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model., Experimental Approach: LUF7244 was tested in vitro for (a) increasing human I Kv11.1 and canine I Kr and (b) decreasing dofetilide-induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block., Key Results: LUF7244 (0.5-10 μM) concentration dependently increased I Kv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on I KIR2.1 , I Nav1.5 , I Ca-L , and I Ks , doubled I Kr , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg -1 ·15 min -1 ) in dogs with sinus rhythm was not proarrhythmic and shortened, non-significantly, repolarization parameters (QTc: -6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide-induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block., Conclusions and Implications: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of K v 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cantú syndrome (CS) is caused by dominant gain-of-function mutation in ATP-dependent potassium channels. Cellular ATP concentrations regulate potassium current thereby coupling energy status with membrane excitability. No specific pharmacotherapeutic options are available to treat CS but I KATP channels are pharmaceutical targets in type II diabetes or cardiac arrhythmia treatment. We have been suggested that I KATP inhibitors, glibenclamide and HMR1098, normalize CS channels. I KATP in response to Mg-ATP, glibenclamide and HMR1098 were measured by inside-out patch-clamp electrophysiology. Results were interpreted in view of cryo-EM I KATP channel structures. Mg-ATP IC 50 values of outward current were increased for D207E (0.71 ± 0.14 mmol/L), S1020P (1.83 ± 0.10), S1054Y (0.95 ± 0.06) and R1154Q (0.75 ± 0.13) channels compared to H60Y (0.14 ± 0.01) and wild-type (0.15 ± 0.01). HMR1098 dose-dependently inhibited S1020P and S1054Y channels in the presence of 0.15 mmol/L Mg-ATP, reaching, at 30 μmol/L, current levels displayed by wild-type and H60Y channels in the presence of 0.15 mmol/L Mg-ATP. Glibenclamide (10 μmol/L) induced similar normalization. S1054Y sensitivity to glibenclamide increases strongly at 0.5 mmol/L Mg-ATP compared to 0.15 mmol/L, in contrast to D207E and S1020P channels. Experimental findings agree with structural considerations. We conclude that CS channel activity can be normalized by existing drugs; however, complete normalization can be achieved at supraclinical concentrations only., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

K IR 2.1 potassium channels, producing inward rectifier potassium current ( I K1 ), are important for final action potential repolarization and a stable resting membrane potential in excitable cells like cardiomyocytes. Abnormal K IR 2.1 function, either decreased or increased, associates with diseases such as Andersen-Tawil syndrome, long and short QT syndromes. K IR 2.1 ion channel protein trafficking and subcellular anchoring depends on intrinsic specific short amino acid sequences. We hypothesized that combining an evolutionary based sequence comparison and bioinformatics will identify new functional domains within the C-terminus of the K IR 2.1 protein, which function could be determined by mutation analysis. We determined PEST domain signatures, rich in proline (P), glutamic acid (E), serine (S), and threonine (T), within K IR 2.1 sequences using the "epestfind" webtool. WT and ΔPEST K IR 2.1 channels were expressed in HEK293T and COS-7 cells. Patch-clamp electrophysiology measurements were performed in the inside-out mode on excised membrane patches and the whole cell mode using AxonPatch 200B amplifiers. K IR 2.1 protein expression levels were determined by western blot analysis. Immunofluorescence microscopy was used to determine K IR 2.1 subcellular localization. An evolutionary conserved PEST domain was identified in the C-terminus of the K IR 2.1 channel protein displaying positive PEST scores in vertebrates ranging from fish to human. No similar PEST domain was detected in K IR 2.2, K IR 2.3, and K IR 2.6 proteins. Deletion of the PEST domain in California kingsnake and human K IR 2.1 proteins (ΔPEST), did not affect plasma membrane localization. Co-expression of WT and ΔPEST K IR 2.1 proteins resulted in heterotetrameric channel formation. Deletion of the PEST domain did not increase protein stability in cycloheximide assays [T½ from 2.64 h (WT) to 1.67 h (ΔPEST), n.s.]. WT and ΔPEST channels, either from human or snake, produced typical I K1 , however, human ΔPEST channels displayed stronger intrinsic rectification. The current observations suggest that the PEST sequence of K IR 2.1 is not associated with rapid protein degradation, and has a role in the rectification behavior of I K1 channels.

Many piezochromic luminescent (PCL) dyes are known for their fluorescent switching capacity in the powdered phase, but they are usually difficult to utilize practically owing to poor mechanical properties. Herein, a nanofiber film fabricated through an electrospinning process is doped with PCL dye. The electrospun film not only reveals the mechanics of macromolecular materials, but also achieves precise, gradient pressure recognition (ratiometric PCL behavior). The PCL sensitivity and color difference of the dye in a crystalline state are calculated to be 15.7 nm GPa -1 and 149 nm, respectively. The sensitivity of an electrospun film containing 0.1 % (w/w) dye decreased to 3.6 nm GPa -1 . Moreover, the individual effects of molecular conformation and intermolecular interaction on the PCL properties have been clearly distinguished through in situ high-pressure experiments. Intermolecular interactions play a more significant role in PCL color difference and sensitivity. The film fabricated through an electrospinning process contributes to understanding of the working mechanism and real applications of piezochromic materials., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. K IR 2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (I K 1 ), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics. Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system. Here we defined the potential interference in K IR 2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited I K 1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased K IR 2.1 expression (2.0 ± 0.2-fold with amiodarone: 10 μM, 24 hrs; 2.3 ± 0.3-fold with dronedarone: 5 μM, 24 hrs) and late-endosomal/lysosomal K IR 2.1 accumulation. Increased K IR 2.1 expression level was also observed in the presence of Na v 1.5 co-expression. Augmented K IR 2.1 protein levels and intracellular accumulation were also observed in COS-7, END-2, MES-1 and EPI-7 cells. Both drugs had no effect on K v 11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at -120 mV, 5 μM) enhanced I KIR 2.1 upon 24-hrs treatment, whereas dronedarone tended to increase I KIR 2.1 and it did not reach significance (43.8 ± 5.5%, P = 0.26 at -120 mV; 2 μM). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced I K 1 by inhibiting K IR 2.1 degradation., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Two novel triphenylacrylonitrile derivatives (TPAN-C2 and TPAN-C3) with highly twisted conformations have been successfully prepared by Suzuki coupling reaction. Both of them show mechanochromic (MC) fluorescent behaviour and exhibit remarkable fluorescence redshifts from sky-blue to light green upon fully grinding them. Interestingly, the ground powders recover their original states upon heating at 100 °C for 1 min or fuming with solvents vapour. Such intriguing MC properties of TPAN-C2 and TPAN-C3 are attributed to their phase transitions between crystalline and amorphous states, which are confirmed by powder X-ray diffraction (XRD) data. Moreover, the behaviour of both TPAN-C2 and TPAN-C3 indicates that the aggregation-induced emission (AIE) gives rise to rather high fluorescence quantum efficiencies (Φ f ) of 0.78 and 0.97, respectively. The influences of stacking mode and molecular conformation on MC properties and the high Φ f of TPAN-C2 and TPAN-C3 are discussed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Myocardial fibrosis contributes to cardiac remodeling and loss of cardiac function in myocardial infarction and heart failure. This study used in vitro and in vivo models to examine the effects of ursolic acid (UA) on myocardial fibrosis and to explore its potential mechanism., Methods: Transverse aortic constriction (TAC) surgery was performed in mice to induce cardiac hypertrophy and fibrosis. UA was orally administered 1 week prior to TAC. Two weeks after TAC, myocardial pathology was detected using Masson's trichrome staining and transmission electron microscopy, and heart-to-body weight ratio was measured. For in vitro studies, cultured cardiac fibroblasts were treated with serum in the presence or absence of UA. The relative levels of miR-21 and p-ERK/ERK, collagen content and cell viability were measured., Results: Ursolic acid attenuated pathological cardiac hypertrophy and myocardial fibrosis in vivo induced by TAC. Downregulation of miR-21 and p-ERK/ERK were observed in myocardial fibroblasts treated with UA in a dose-dependent manner compared with the control group both in vitro and in vivo., Conclusions: Our study demonstrates that UA can inhibit myocardial fibrosis both in vitro and in vivo, and the effects of UA on myocardial fibrosis may be due to the inhibition of miR-21/ERK signaling pathways., (© 2015 John Wiley & Sons Ltd.)

Background and Purpose: Statins decrease heart disease risk, but their mechanisms are not completely understood. We examined the role of the TGF-β receptor III (TGFBR3) in the inhibition of cardiac fibrosis by simvastatin., Experimental Approach: Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice given simvastatin orally for 7 days. Cardiac fibrosis was measured by Masson staining and electron microscopy. Heart function was evaluated by echocardiography. Signalling through TGFBR3, ERK1/2, JNK and p38 pathways was measured using Western blotting. Collagen content and cell viability were measured in cultures of neonatal mouse cardiac fibroblasts (NMCFs). Interactions between TGFBR3 and the scaffolding protein, GAIP-interacting protein C-terminus (GIPC) were detected using co-immunoprecipitation (co-IP). In vivo, hearts were injected with lentivirus carrying shRNA for TGFBR3., Key Results: Simvastatin prevented fibrosis following MI, improved heart ultrastructure and function, up-regulated TGFBR3 and decreased ERK1/2 and JNK phosphorylation. Simvastatin up-regulated TGFBR3 in NMCFs, whereas silencing TGFBR3 reversed inhibitory effects of simvastatin on cell proliferation and collagen production. Simvastatin inhibited ERK1/2 and JNK signalling while silencing TGFBR3 opposed this effect. Co-IP demonstrated TGFBR3 binding to GIPC. Overexpressing TGFBR3 inhibited ERK1/2 and JNK signalling which was abolished by knock-down of GIPC. In vivo, suppression of cardiac TGFBR3 abolished anti-fibrotic effects, improvement of cardiac function and changes in related proteins after simvastatin., Conclusions and Implications: TGFBR3 mediated the decreased cardiac fibrosis, collagen deposition and fibroblast activity, induced by simvastatin, following MI. These effects involved GIPC inhibition of the ERK1/2/JNK pathway., (© 2015 The British Pharmacological Society.)