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Gap junctions (GJs) formed by connexins (Cxs) in T lymphocytes have been reported to have important roles in the T lymphocyte-driven inflammatory response and hypertension-mediated inflammation. Estrogen has a protective effect on cardiovascular diseases, including hypertension and it attenuates excessive inflammatory responses in certain autoimmune diseases. However, the mechanisms involved in regulating the pro-inflammatory response are complex and poorly understood. The current study investigated whether β-estradiol suppresses hypertension and pro-inflammatory stimuli-mediated inflammatory responses by regulating Cxs and Cx-mediated GJs in peripheral blood lymphocytes. Male, 16-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats were randomly divided into the following three groups: WKY rats, vehicle (saline)-treated SHRs, and β-estradiol (20 µg/kg/day)-treated SHRs. β-estradiol was administered subcutaneously for 5 weeks. Hematoxylin and eosin staining was performed to evaluate target organ injury. Flow cytometry and ELISA were used to measure the populations of T lymphocyte subtypes in the peripheral blood, and expression of Cx40/Cx43 in T cell subtypes, and pro-inflammation cytokines levels, respectively. ELISA, a dye transfer technique, immunofluorescence and immunoblotting were used to analyze the effect of β-estradiol on pro-inflammatory cytokine secretion, Cx-mediated GJs and the expression of Cxs in concanavalin A (Con A)-stimulated peripheral blood lymphocytes isolated from WKY rat. β-estradiol significantly decreased blood pressure and inhibited hypertension-induced target organ injury in SHRs. Additionally, β-estradiol treatment significantly improved the immune homeostasis of SHRs, as demonstrated by the decreased percentage of cluster of differentiation (CD)4+/CD8+ T-cell subset ratio, reduced serum levels of pro-inflammatory cytokines and increased the percentage of CD4+CD25+ T cells. β-estradiol also markedly reduced the expression of Cx40/Cx43 in T lymphocytes from SHRs. In vitro, β-estradiol significantly suppressed the production of pro-inflammatory cytokines, reduced communication via Cx-mediated gap junctions and decreased the expression of Cx40/Cx43 in Con A-stimulated lymphocytes. These results indicate that β-estradiol attenuates inflammation and end organ damage in hypertension, which may be partially mediated via downregulated expression of Cxs and reduced function of Cx-mediated GJ. [ABSTRACT FROM AUTHOR]

Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. [ABSTRACT FROM AUTHOR]

The mass-front velocities of granular flows results from the joint action of particle size gradations and the underlying surfaces. However, because of the complexity of friction during flow movement, details such as the slope-toe impedance effects and momentum-transfer mechanisms have not been completely explained by theoretical analyses, numerical simulations, or field investigations. To study the mass-front velocity of dry granular flows influenced by the angle of the slope to the runout plane and particle size gradations we conducted model experiments that recorded the motion of rapid and long-runout rockslides or avalanches. Flume tests were conducted using slope angles of 25°, 35°, 45°, and 55° and three particle size gradations. The resulting mass-front motions consisted of three stages: acceleration, velocity maintenance, and deceleration. The existing methods of velocity prediction could not explain the slowing effect of the slope toe or the momentum-transfer steady velocity stage. When the slope angle increased from 25° to 55°, the mass-front velocities dropped significantly to between 44.4% and 59.6% of the peak velocities and energy losses increased from 69.1% to 83.7% of the initial, respectively. The velocity maintenance stages occurred after the slope-toe and mass-front velocity fluctuations. During this stage, travel distances increased as the angles increased, but the average velocity was greatest at 45°. At a slope angle of 45°, as the median particle size increased, energy loss around the slope toe decreased, the efficiency of momentum transfer increased, and the distance of the velocity maintenance stage increased. We presented an improved average velocity formula for granular flow and a geometrical model of the energy along the flow line. [ABSTRACT FROM AUTHOR]

To investigate the nanoscale mechanical properties of exfoliated cervical epithelial cells from patients to further reveal the pathogenesis of cervical cancer and help early diagnose. Exfoliated cells were collected from nine patients with chronic cervicitis or CIN1(control group), 30 patients with CIN2-3 (CIN 2-3 group), and 13 patients with cervical cancer (cervical cancer group). Stiffness of the cells was determined by atomic force microscope (AFM). Expression of P16INK4A was studied by immunocytochemistry. Environmental scanning electron microscopy was performed to observe the surface microtopography of the exfoliated cells. Young's modulus was measured for cells exfoliated from control and patients with CIN 2-3 and cervical cancer by AFM. The results showed that with increasing cervical lesions, the Young's modulus of the exfoliated cervical cells increased ( P < 0.05). The modulus of the exfoliated cells was significantly decreased in the three patients 1 year after the surgery compared with the value before the surgery. Expression of P16INK4A in the exfoliated cells had not been statistically significant. Squamous cells from cervical cancer group had dense and disordered microvilli without clear microridges compare to other groups. The Young's modulus is increased from the control group, to CIN2-3 and cervical cancer groups, suggesting that the stiffness of cervical epithelial cells increases gradually with increasing cervical lesions. The changes in the mechanical properties of the exfoliated cells occur earlier than the changes in cell morphology. Therefore, analysis of mechanical properties of the exfoliated cells may be used to aid early diagnosis of the cancer. [ABSTRACT FROM AUTHOR]

β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors ( β2- TG), and the effect of cardiac pressure overload. β2- TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2- TGs showed upregulated expression of vascular endothelial growth factor ( VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein ( CREB), and increased recruitment of phospho- CREB, CREB-binding protein ( CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction ( TAC), angiogenic signaling in β2- TGs was inhibited within 1 week after TAC. β2- TG hearts, but not controls, exposed to pressure overload for 1-2 weeks showed significant increases from baseline in phosphorylation of Ca2+/calmodulin-dependent kinase II (Ca MKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho- CREB, p300 and CBP recruited to the CREB-responsive element ( CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non- TG mice with TAC developed compensatory hypertrophy, (2- TGs exhibited exaggerated hypertrophic growth at week-1 post- TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2 AR/ CREB/ VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated Ca MKII and p53, leading to impaired angiogenesis and functional decompensation. [ABSTRACT FROM AUTHOR]

Purpose: Relaxin, a new drug for heart failure therapy, exerts its cardiac actions through relaxin family peptide receptor 1 (RXFP1). Factors regulating RXFP1 expression remain unknown. We have investigated effects of activation of adrenoceptors (AR), an important modulator in the development and prognosis of heart failure, on expression of RXFP1 in rat cardiomyocytes and mouse left ventricles (LV). Methods: Expression of RXFP1 at mRNA (real-time PCR) and protein levels (immunoblotting) was measured in cardiomyocytes treated with α- and β-AR agonists or antagonists. RXFP1 expression was also determined in the LV of transgenic mouse strains with cardiac-restricted overexpression of α-, α- or β-AR. Specific inhibitors were used to explore signal pathways involved in α-AR mediated regulation of RXFP1 in cardiomyocytes. Results: In cultured cardiomyocytes, α-AR stimulation resulted in 2-3 fold increase in RXFP1 mRNA ( P < 0.001), which was blocked by specific inhibitors for protein kinase C (PKC) or mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK). Activation of β-, but not β-AR, significantly inhibited RXFP1 expression ( P < 0.001). Relative to respective wild-type controls, RXFP1 mRNA levels in the LV of mice overexpressing α- or α-AR were increased by 3- or 10-fold, respectively, but unchanged in β-AR transgenic hearts. Upregulation by α-AR stimulation RXFP1 expression was confirmed at protein levels both in vitro and in vivo. Conclusions: Expression of RXFP1 was up-regulated by α-AR but suppressed by β-AR, mainly β-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure. [ABSTRACT FROM AUTHOR]

Chronic injection with the β-adrenoceptor (β- AR) agonist isoproterenol ( ISO) has been commonly used as an animal model of β- AR-induced cardiac remodelling and heart failure. This ISO-treated model usually exhibits significantly decreased conscious heart rate ( HR). However, the HR in treatment groups is usually adjusted to the same levels by anaesthesia to assess cardiac geometry and function. In the present study, we report a method of echocardiographic assessment that represents the true cardiac geometry and function under conditions of ISO withdrawal., Briefly, C57BL/6 mice were treated with 5 mg/kg per day ISO for 12 weeks. Cardiac geometry and function were assessed by high-resolution echocardiography in vehicle (saline) - and ISO-treated mice that were either conscious or anaesthetized using different concentrations of isoflurane., The cardiac β- AR response was decreased in ISO-treated mice, as evidenced by markedly decreased conscious HR. Vehicle- and ISO-treated mice did not differ in terms of cardiac geometry or function when HR was adjusted to the same level (400 b.p.m.) in both treatment groups, but cardiac geometry and function did differ when a low (1%) rather than high (1.5% or 2%) isoflurane concentration was used to adjust HR. Furthermore, 3 day ISO withdrawal eliminated the difference in conscious HR between the two groups. In addition, the groups differed in cardiac geometry and function regardless of the isoflurane concentration used., In conclusion, using isoflurane to decrease the HR of treated groups to the same level may mask left ventricular dysfunction in ISO-treated mice. Withdrawal of ISO eliminated the difference in basal HR between the ISO-treated and control groups on echocardiography, allowing a more accurate assessment of cardiac pathological and functional changes. [ABSTRACT FROM AUTHOR]

Aims Chronic heart failure is a complex clinical syndrome with impaired myocardial contractility. In failing cardiomyocytes, decreased signalling efficiency between the L-type Ca2+ channels (LCCs) in the plasma membrane (including transverse tubules, TTs) and the ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) underlies the defective excitation–contraction (E–C) coupling. It is therefore intriguing to know how the LCC–RyR signalling apparatus is remodelled in human heart failure. Methods and results Stereological analysis of transmission electron microscopic images showed that the volume densities and the surface areas of TTs and junctional SRs were both decreased in heart failure specimens of dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). The TT–SR junctions were reduced by ∼60%, with the remaining displaced from the Z-line areas. Moreover, the spatial span of individual TT–SR junctions was reduced by ∼17% in both DCM and ICM tissues. In accordance with these remodelling, junctophilin-2 (JP2), a structural protein anchoring SRs to TTs, was down-regulated, and miR-24, a microRNA that suppresses JP2 expression, was up-regulated in both heart failure tissues. Conclusion Human heart failure of distinct causes shared similar physical uncoupling between TTs and SRs, which appeared attributable to the reduced expression of JP2 and increased expression of miR-24. Therapeutic strategy against JP2 down-regulation would be expected to protect patients from cardiac E–C uncoupling. [ABSTRACT FROM PUBLISHER]

Aims The contraction of a heart cell is controlled by Ca2+-induced Ca2+ release between L-type Ca2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC–RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC–RyR signalling and contractility. Methods and results In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT–SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT–SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca2+ release activation. Conclusions The shrinking and eventual absence of TT–SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca2+ release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT–SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies. [ABSTRACT FROM AUTHOR]

Aim:To investigate the molecular mechanisms underlying the antitumor activity of cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata.Methods:Human osteosarcoma cell line SaOS2 was used. MTT assay, Hoechst 33342 nuclear staining, flow cytometry, Western blotting and nude mouse xenografts of SaOS2 cells were applied to examine the antitumor activity of CEP in vitro and in vivo. The expression levels of STAT3 and its downstream signaling molecules were measured with Western blotting and immunochemistry analysis. The activity of STAT3 was detected based on the phosphorylation level of STAT3, luciferase gene reporter assay and translocation of STAT3 to the nucleus.Results:Treatment of SaOS2 cells with CEP (2.5-20 μmol/L) inhibited the cell growth in a concentration- and time-dependent manner. CEP (10 μmol/L) caused cell cycle arrest at G1 phase and induced apoptosis of SaOS2 cells. CEP (10 and 15 μmol/L) significantly decreased the expression of STAT3 in SaOS2 cells. Furthermore, CEP (5 and 10 μmol/L) significantly inhibited the expression of target genes of STAT3, including the anti-apoptotic gene Bcl-xL and the cell cycle regulators c-Myc and cyclin D1. In nude mouse xenografts of SaOS2 cells, CEP (20 mg·kg−1·d−1, ip for 19 d) significantly reduced the volume and weight of the tumor.Conclusion:Our findings suggest that inhibition of STAT3 signaling pathway is involved in the anti-tumor activity of CEP. [ABSTRACT FROM AUTHOR]

Aim:To study and establish a proteome reference map and regulation network of neonatal rat cardiomyocyte.Methods:Cultured cardiomyocytes of neonatal rats were used. All proteins expressed in the cardiomyocytes were separated and identified by two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Biological networks and pathways of the neonatal rat cardiomyocytes were analyzed using the Ingenuity Pathway Analysis (IPA) program (www.ingenuity.com). A 2-DE database was made accessible on-line by Make2ddb package on a web server.Results:More than 1000 proteins were separated on 2D gels, and 148 proteins were identified. The identified proteins were used for the construction of an extensible markup language-based database. Biological networks and pathways were constructed to analyze the functions associate with cardiomyocyte proteins in the database. The 2-DE database of rat cardiomyocyte proteins can be accessed at http://2d.bjmu.edu.cn.Conclusion:A proteome reference map and regulation network of the neonatal rat cardiomyocytes have been established, which may serve as an international platform for storage, analysis and visualization of cardiomyocyte proteomic data. [ABSTRACT FROM AUTHOR]

Aim:To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.Methods:Wild type and AMPKα2 knockout (AMPKα2−/−) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg−1·d−1) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting.Results:Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2−/− mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2−/− mice.Conclusion:Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

1. The purpose of the present study was to evaluate differences in the AMP-activated protein kinase (AMPK) phosphorylation sites in cardiac hypertrophy induced byl-thyroxine and angiotensin (Ang) II. 2. Cardiac hypertrophy was induced in wild-type and AMPKα2-knockout mice by treatment with 1 mg/kg, i.p., thyroxine or 1.44 mg/kg per day AngII for 14 days. The phenotype of the hypertrophy was evaluated using echocardiographic measurments and histological analyses. The phosphorylation of AMPK at α-Ser485/491 and α-Thr172 was determined by western blot analysis. 3. In wild-type mice, the phosphorylation of AMPKα-Ser485/491 was significantly elevated in the AngII-treated group, but not in the thyroxine-reated group, compared with the vehicle control group. In contrast, the phosphorylation of AMPKα-Thr172 was significantly increased by thyroxine, but not AngII, treatment compared with the vehicle control group. Furthermore, knockout of the AMPKα2 subunit abolished phosphorylation at the α-Ser485/491 site and significantly suppressed phosphorylation at the α-Thr172 site, resulting in alleviation of thyroxine- but not AngII-induced hypertrophy. 4. In conclusion,l-thyroxine and AngII induce the phosphorylation of distinct sites of AMPK in cardiac hypertrophy. Phosphorylation of AMPK α-Thr172 may contribute to thyroxine-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Abstract: Hsp60 is an important component of defense mechanisms against diabetic myocardial injury; however, the cause of Hsp60 reduction in the diabetic myocardium remains unknown. After stimulation of cardiomyocytes with high glucose in vivo and in vitro, significant up-regulation of miR-1/miR-206 and post-transcriptional modulation of Hsp 60 were observed. Serum response factor (SRF) and the MEK1/2 pathway were involved in miR-1 and miR-206 expression in cardiomyocytes. miR-1 and miR-206 regulated Hsp60 expression post-transcriptionally and accelerated cardiomyocyte apoptosis through Hsp60. These results revealed that miR-1 and miR-206 regulate Hsp60 expression, contributing to high glucose-mediated apoptosis in cardiomyocytes. [ABSTRACT FROM AUTHOR]

1. The mouse is the preferred species for gene targeting as a tool for research into the heart and heart development. The developmental features of the geometry and function of the heart in young mice are not well defined and cardiac functional responses following stimulation of β-adrenoceptors have not been investigated. 2. Using the VisualSonic (Toronto, ON, Canada) high-resolution ultrasound system, we investigated male C57BL/6 mice at 0.5–18 weeks of age. Echocardiography was performed at baseline and repeated after administration of the β-adrenoceptor agonist isoproterenol (4 μg/kg). 3. The geometry of the left ventricle became mature 2 weeks after birth. A significant decline in left ventricular contractile function occurred at 2–3 weeks of age. 4. Inotropic and chronotropic responses to isoproterenol were significantly weaker in mice at a weaning age < 2 weeks compared with adult mice (heart rate increment 3 ± 3% vs 32 ± 4%, respectively; fractional shortening increment 19 ± 5% vs 78 ± 8%, respectively; P < 0.001). 5. In conclusion, significant changes occur in mice from birth until weaning with respect to the topography, function and β-adrenoceptor responsiveness of the heart. The results of the present study provide a reference point for future studies in genotyping cardiac function during the postnatal phase in genetically engineered mice. [ABSTRACT FROM AUTHOR]

1. Insulin-like growth factor (IGF)-I plays an important role in the pathogenesis of heart disease and has been shown to strongly induce the proliferation of cardiac fibroblasts (CFs). It remains unknown whether 14-3-3 proteins, which are associated the regulation of signal transduction, affect IGF-I-induced CF proliferation. 2. In the present study, we investigated the effects of 14-3-3 proteins on CF proliferation in response to IGF-I. Proliferation of CFs was determined by cell counting and a bromodeoxyuridine incorporation assay. Phosphorylation of signalling molecules was evaluated by western blottling. Activity of nuclear factor of activated T cells (NFAT) was examined using a dual luciferase reporter gene assay and immunofluorescence. 3. It was found that adenovirus-mediated transfection of YFP-R18 peptide (AdR18), a known inhibitor of 14-3-3, significantly enhanced IGF-I-induced CF proliferation. This potentiation arose from an increase in phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and AKT (protein kinase B), inactivation of glycogen synthesis kinase (GSK) 3β and increased NFAT activity. 4. Collectively, the results of the present study suggest that 14-3-3 proteins inhibit IGF-I-induced CF proliferation via a PI3-K-dependent NFAT signalling pathway. This finding may contribute to our understanding of the function of 14-3-3 proteins in the heart. [ABSTRACT FROM AUTHOR]

1. Ketamine is widely used for the induction of anaesthesia in high-risk patients with cardiovascular instability or severe hypovolaemia. However, the ionic mechanisms involved in the effects of ketamine at therapeutically relevant concentrations in human cardiac myocytes are unclear. The present study was designed to investigate the effects of ketamine on L-type Ca2+ (ICa), transient outward K+ (Ito), ultra-rapid delayed rectifier K+ (IKur) and inward rectifier potassium (IK1) currents, as well as on action potentials, in human isolated atrial myocytes. 2. Atrial myocytes were isolated enzymatically from specimens of human atrial appendage obtained from patients undergoing coronary artery bypass grafting. The action potential and membrane currents were recorded in both current- and voltage-clamp modes using the patch-clamp technique. 3. Ketamine inhibited ICa with an IC50 of 1.8 µmol/L. In addition, 10 µmol/L ketamine decreased the ICa peak current at +10 mV from 5.1 ± 0.3 to 2.1 ± 0.4 pA/pF ( P < 0.01), but did not change the threshold potential, peak current potential and reverse potential. 4. Ketamine had no effect on Ito, IKur or IK1, but it reversibly shortened the duration of the action potential in human atrial myocytes. 5. In conclusion, ketamine, at a clinically relevant concentration, shortens the action potential duration of the human atrial myocytes, probably by inhibiting ICa. [ABSTRACT FROM AUTHOR]

1. In the present review, we focus on the genetic mouse models for transforming growth factor (TGF)-β signalling, which have aided our understanding on the role of the TGF-β signalling pathway in cardiac hypertrophy/fibrosis and the molecular mechanisms involved. 2. Knockout of TGF-β is embryonic lethal, indicating that TGF-β signalling plays an important role in embryonic development. In order to avoid this defect, many mouse strains with cardiac-specific targeted genes in TGF-β signalling have been developed. 3. The TGF-β family signalling pathway includes Smad-dependent and -independent pathways. 4. Investigations using the genetic mouse models have confirmed and uncovered the involvement of the TGF-β/TGF-β-activated kinase 1 (TAK1) pathway in the development of cardiac hypertrophy and fibrosis. Although the downstream cascade of TAK1-induced cardiac hypertrophy remains only partially defined, recent research indicates that the TGF-β/TAK1/p38 pathway is involved in cardiac fibrosis 5. Smad-dependent signalling may not be involved in, or may even be inhibitory for, cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β2-adrenergic receptors (β2-ARs) are important targets in COPD therapy. β2-adrenergic receptor autoantibodies (β2-AAbs), which may directly affect β2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2-AAbs are associated with smoking-related emphysema. [ABSTRACT FROM AUTHOR]