Inhibition of nuclear factor κB in the lungs protect bleomycin-induced lung fibrosis in mice.

BACKGROUND: Pulmonary fibrosis is a debilitating condition with limited therapeutic avenues. The pathogenicity of pulmonary fibrosis constitutes involvement of cellular proliferation, activation, and transformational changes of fibroblast to myofibroblasts. It is a progressive lung disease and is primarily characterized by aberrant accumulation of extracellular matrix proteins in the lungs with poor prognosis. The inflammatory response in the pathogenesis of lung fibrosis is suggested because of release of several cytokines; however, the underlying mechanism remains undefined. A genetic model is the appropriate way to delineate the underlying mechanism of pulmonary fibrosis. METHODS AND RESULTS: In this report, we have used cc-10 promoter based IκBα mutant mice (IKBM, an inhibitor of NF-κB) which were challenged with bleomycin (BLM). Compared to wild-type (WT) mice, the IKBM mice showed significant reduction in several fibrotic, vascular, and inflammatory genes. Moreover, we have identified a new set of dysregulated microRNAs (miRNAs) by miRNA array analysis in BLM-induced WT mice. Among these miRNAs, let-7a-5p and miR-503-5p were further analyzed. Our data showed that these two miRNAs were upregulated in WT-BLM and were reduced in IKBM-BLM mice. Bioinformatic analyses showed that let-7a-5p and miR-503-5p target for endothelin1 and bone morphogenic receptor 1A (BMPR1A), respectively, and were downregulated in WT-BLM mice indicating a link in pulmonary fibrosis. CONCLUSION: We concluded that inhibition of NF-κB and modulation of let-7a-5p and miR-503-5p contribute a pivotal role in pulmonary fibrosis and may be considered as possible therapeutic target for the clinical management of lung fibrosis.

NF-κB mediated miR-130a modulation in lung microvascular cell remodeling: Implication in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease which is associated with pulmonary arterial endothelial cells (PAEC) dysfunction and pulmonary arterial smooth muscle cells proliferation. Moreover, inflammation is contributing a critical role in EC dysfunction and remains elusive. Nuclear factor-kappa B (NF-κB) is a master transcriptional regulator in various cardiovascular pathologies; but, NF-κB's role in EC dysfunction in unknown. Our previous study using cardiac and lung specific IκBα mutant mice (3M and IKBM) showed that PAH induced right ventricular hypertrophy (RVH) was prevented in monocrotaline (MCT) treated 3M and IKBM mice, compared to the wild-type mice. Recently, microRNAs (miRNAs) have emerged as a new class of post-transcriptional regulators in vascular remodeling; but, NF-κB regulated miRNA modulation in EC dysfunction is unknown. Using miRNA array analysis, we identified miR-130a which is upregulated in MCT-induced PAH mouse model, as a possible candidate to study. We showed that overexpressing miR-130a in lung microvascular endothelial cells (MVEC) promoted activation of α-smooth muscle actin, a critical component in endothelial-to-mesenchymal transition in EC remodeling. In this study, we demonstrated that bone morphogenetic protein receptor 2 (BMPR2) was a target for miR-130a and miR-130a was regulated by NF-κB which controlled apoptosis and vascular genes in MVEC. The findings reveal that NF-κB-mediated miR-130a modulation is critical in lung vascular remodeling.

The pseudoactive site of ILK is essential for its binding to alpha-Parvin and localization to focal adhesions.

Integrin-linked kinase (ILK) plays a pivotal role in connecting transmembrane receptor integrin to the actin cytoskeleton and thereby regulating diverse cell-adhesion-dependent processes. The kinase domain (KD) of ILK is indispensable for its function, but the underlying molecular basis remains enigmatic. Here we present the crystal structure of the ILK KD bound to its cytoskeletal regulator, the C-terminal calponin homology domain of alpha-parvin. While maintaining a canonical kinase fold, the ILK KD displays a striking pseudoactive site conformation. We show that rather than performing the kinase function, this conformation specifically recognizes alpha-parvin for promoting effective assembly of ILK into focal adhesions. The alpha-parvin-bound ILK KD can simultaneously engage integrin beta cytoplasmic tails. These results thus define ILK as a distinct pseudokinase that mechanically couples integrin and alpha-parvin for mediating cell adhesion. They also highlight functional diversity of the kinase fold and its "active" site in mediating many biological processes.

Thymosin ß4 Prevents Angiotensin II-Induced Cardiomyocyte Growth by Regulating Wnt/WISP Signaling.

Thymosin beta-4 (Tß4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tß4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio-protective effect of Tß4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tß4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, ß-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tß4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tß4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tß4. This is the first report which demonstrates that Tß4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. © 2015 Wiley Periodicals, Inc.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

NF-κB-mediated miR-30b regulation in cardiomyocytes cell death by targeting Bcl-2.

Angiotensin II(Ang II)-stimulated cardiomyocytes hypertrophy and apoptosis are associated with nuclear factor-κB (NF-κB) activation. NF-κB, a redox-sensitive transcription factor, contributes a critical role in cell death, but, Ang II-stimulated NF-κB-mediated cardiomyocytes apoptosis remains less understood. Recently, microRNAs (miRNAs) have been shown to be critical regulators in various cardiac remodeling processes; however, NF-κB-mediated miRNA's role in cardiomyocytes apoptosis remains undetermined. The miR-30b has been implicated in diverse cardiac remodeling; but, NF-κB-mediated miR-30b modulation in Ang II-induced cardiomyocytes death is currently unknown. In the present study, neonatal cardiomyocytes were pretreated with SN50, a selective cell permeable peptide inhibitor of NF-κB, or transfected with miR-30b mimetic and inhibitors separately, and then challenged with Ang II. The target gene, Bcl-2, and NF-κB transcriptional activity were analyzed. Our results demonstrated that NF-κB positively regulated miR-30b expression in Ang II-induced cardiomyocytes apoptosis, and Bcl-2 was a direct target for miR-30b. NF-κB further regulated the expression of Bcl-2 in the above setting. Furthermore, Ang II-induced cardiomyocytes apoptosis rescued by inhibiting either NF-κB or miR-30b provided an important role in cardiomyocytes cell death. We evaluated a critical role of NF-κB-mediated miR-30b modulation in Ang II-stimulated cardiomyocytes targeting Bcl-2. Our data may provide a new insight of miR-30b's role in myocardial infarction or ischemia.

NF-κB mediated miR-26a regulation in cardiac fibrosis.

Micro-RNAs (miRNAs) are a class of small non-coding RNAs, recently emerged as a post-transcriptional regulator having a key role in various cardiac pathologies. Among them, cardiac fibrosis that occurs as a result from an imbalance of extracellular matrix proteins turnover and is a highly debilitating process that eventually lead to organ dysfunction. An emerging theme on is that miRNAs participate in feedback loop with transcription factors that regulate their transcription. NF-κB, a key transcription factor regulator controls a series of gene program in various cardiac diseases through positive and negative feedback mechanism. But, NF-κB mediated miRNA regulation in cardiac fibrosis remains obscure. Bioinformatics analysis revealed that miR-26a has targets collagen I and CTGF and possesses putative NF-κB binding element in its promoter region. Here, we show that inhibition of NF-κB in cardiac fibroblast restores miR-26a expression, attenuating collagen I, and CTGF gene expression in the presence of Ang II, conferring a feedback regulatory mechanism in cardiac fibrosis. The target genes for miR-26a were confirmed using 3'-UTR luciferase reporter assays for collagen I and CTGF genes. Using NF-κB reporter assays, we determine that miR-26a overexpression inhibits NF-κB activity. Finally, we show that miR-26a expression is restored along with the attenuation of collagen I and CTGF genes in cardiac specific IkBa triple mutant transgenic mice (preventing NF-κB activation) subjected to 4 weeks transverse aortic banding (TAC), compared to wild type (WT) mice. The data indicate a potential role of miR-26a in cardiac fibrosis and, offer novel therapeutic intervention.

Circulating miRNA as novel markers for diastolic dysfunction.

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. Though their significance is unclear, pioneer profiling studies have attributed specific serum miRNA signatures to different disease conditions. The diagnostic potential of miRNA detection in human plasma for cardiovascular disorders is beginning to be recognized as important. In this study, we examined miRNA profiling in isolated diastolic dysfunction (DD) with preserved systolic function to identify promising candidate miRNAs. The presence of these miRNAs was tested in stable patients with isolated DD, patients with stable compensated dilated cardiomyopathy (DCM-systolic plus diastolic dysfunction) and those with decompensated congestive heart failure secondary to dilated cardiomyopathy (DCM-CHF-systolic plus diastolic dysfunction). We identified new circulating miRNAs (miR-454, miR-500, miR-1246, miR-142-3p) which showed distinct patterns of expression in patients with diastolic dysfunction. The presence or absence of systolic dysfunction does not seem to affect this trend. MiR-454 and miR-500 are downregulated in diastolic dysfunction. MiR-1246 is upregulated in diastolic dysfunction. MiR-142-3p is downregulated in DCM and DCM-CHF groups but not in the DD group. The expression of miR-124-5p is highly upregulated in DCM but not in DD and DCM-CHF groups. We therefore propose that these circulating miRNAs may serve as novel biomarkers for diastolic dysfunction because in all of these patients the only common factor was diastolic dysfunction.

Effect of thymosin ß4 on lipopolysaccharide­stimulated brain microvascular endothelial cell remodeling: A possible role in blood­brain barrier injury.

War veterans, in particular, are more prone to mental illness as they are more likely to have encountered multiple traumatic brain injuries (TBIs) whilst serving on active duty in war zone areas. A TBI is known to cause mortality or serious neurological disabilities among survivors and elicits a number of pathological processes, including neuroinflammation and blood brain barrier (BBB) disruption, leading to secondary brain damage and subsequent impairment of the neurovascular unit. Although several drugs exhibit promising effects for TBI, the repertoire of currently available therapeutic strategies remains limited. Thymosin 4 (Tß4) is a 43-amino acid G-acting sequestering peptide that confers neuroprotective potential in TBI models. However, its role in BBB function remains unclear. Further research into the mechanism of BBB disruption induced by TBI and its specific role in neurovascular pathophysiology is necessary. In the present study, the protective effects of Tß4 in lipopolysaccharide (LPS)-stimulated gene expression of several tight junction proteins, inflammatory genes, apoptotic genes, and adhesion genes in human brain microvascular endothelial cells (hBMVECs), one of the pivotal cell types in the BBB, were reported. The results suggested that pretreatment with Tß4 reversed the LPS-induced damage of BBB components in hBMVECs. Furthermore, these results identified neuregulin 1 as a possible target for Tß4. Therefore, it is proposed that Tß4-mediated cellular signaling in hBMVEC may be vital for understanding the association between the BBB and TBI pathophysiology, which warrants further investigation.

Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline.

Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been performed to assess the genetic, biochemical, and morphological components that contribute to PAH. Despite major advances in the understanding of the pathogenesis of PAH, the molecular mechanism(s) by which PAH promotes RVH and cardiac failure still remains elusive. Of all the mechanisms involved in the pathogenesis, inflammation and oxidative stress remain the core of the etiology of PAH that leads to development of RVH (Dorfmüller P, Perros F, Balabanian K, Humbert M. Eur Respir J 22: 358-363, 2003).

Involvement of Nuclear Factor-κB in Inflammation and Neuronal Plasticity Associated with Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition which develops either due to stress or witnessing a traumatic situation. PTSD is characterized by acute and chronic stress response exhibit anxiety, fear, and an increased inflammatory etiology. Inflammation contributes a critical role in several parts of the brain that control fear and flashback cognatic function. It is known that impairment of the neurological circuit leads to the development of PTSD. Evidence has suggested that dysregulation of the sympathetic nervous system and hypothalamic-pituitary adrenal (HPA) axis and inflammatory responsiveness are pivotal and a greater risk in PTSD. NF-κB, a master regulator for inflammation, has been showed to modulate memory reconsolidation and synaptic plasticity; however, NF-κB's association with PTSD remain elusive. In this review, we provide relevant findings regarding NF-κB activity in various components of brain and describe a potential mechanism linking PTSD using preclinical and clinical models. We envisage NF-κB signaling as a crucial mediator for inflammation, cognitive function, memory restoration and behavioral actions of stress and suggest that it could be used for therapeutic intervention in PTSD.

MicroRNAs as biomarker and novel therapeutic target for posttraumatic stress disorder in Veterans.

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder for military Veterans, characterized by hyperarousal, intrusive thoughts, flashbacks, hypervigilance, and distress after experiencing traumatic events. Some of the known physiological effects of PTSD include hypothalamic-pituitary-adrenal (HPA)-axis imbalance, a cortical function resulting in neuronal deficit and changes in behavior. Moreover, excessive discharge of inflammatory molecules and a dysregulated immune system are implicated in the pathophysiology of PTSD. Due to complex nature of this disorder, the biological underpinnings of PTSD remain inexplicable. Investigating novel biomarkers to understanding the pathogenesis of PTSD may reflect the underlying molecular network for therapeutic use and treatment. Circulatory microRNAs (miRNAs) and exosomes are evolving biomarkers that have shown a key role in psychiatric and neurological disorders including PTSD. Given the unique nature of combat trauma, as well as evidence that a large portion of Veterans do not benefit from frontline treatments, focus on veterans specifically is warranted. In the present review, we delineate the identification and role of several miRNAs in PTSD among veterans. An association of miRNA with HPA-axis regulation through FKBP5, a key modulator in PTSD is discussed as an emerging molecule in psychiatric diseases. We conclude that miRNAs may be used as circulatory biomarker detection in Veterans with PTSD.

Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure.

Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice. However, as the disease progresses, cardiomyocytes show deterioration in some mitochondrial as well as myofibril features, evidenced by swelling of mitochondria, misalignment of myofibril structure, and blurring as well as breakage of Z-lines. At 36 weeks of age, Tg mice (the group in transition from hypertrophy to HF) show significant degenerative changes in cardiomyocytes, including swelling of mitochondria, disruption of the nuclear membrane, and absence of myofibril structure. Besides these, formation of myelin bodies was also observed, a feature typically found in human hearts with HF. Changes in Z-line architecture were further confirmed by alteration in the gene expression profile of desmin and tubulin, the two main cytoskeletal proteins. We thus conclude that Tg mice overexpressing myotrophin show no visible changes in the initiation phase (4 weeks); however, as the disease progresses, alterations in the cytoskeleton are found during the transition phase from hypertrophy to HF (36 weeks onward). Our data suggest that treatment for prevention/reversal of hypertrophy should start at the early stage of hypertrophy to prevent its transition to HF.

Retraction Note: Role of the NF-κB signaling cascade and NF-κB-targeted genes in failing human hearts.

The Editor-in-Chief has retracted this article [1] because a number of lanes in Figs. 3, 4 and 6 of this article are duplicated.

Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.

Myotrophin-induced activation of NF-kappaB has been shown to be associated with cardiac hypertrophy (CH) that progresses to heart failure (HF). In the present study, we examined the cause-and-effect relationship between myotrophin and NF-kappaB activation using small hairpin RNA (shRNA) against myotrophin both in vitro (using neonatal rat myocytes) and in vivo [using myotrophin transgenic (Myo-Tg) mice, which overexpress myotrophin in the heart, develop CH, and gradually progress to HF]. Among several lentiviral vectors expressing myotrophin shRNAs, L-sh-109 showed the best silencing effect at both the mRNA (155.3 +/- 5.9 vs. 32.5 +/- 5.5, P < 0.001) and protein levels associated with a significant reduction of atrial natriuretic factor (ANF) and NF-kappaB. In vivo, when L-sh-109 was delivered directly into the hearts of 10-wk-old Myo-Tg mice, we observed a significant regression of cardiac mass (8.0 vs. 5.7 mg/g, P < 0.001) and myotrophin gene expression (54.5% over untreated Myo-Tg mice, P < 0.001) associated with a reduction in ANF and NF-kappaB signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-kappaB activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.

Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NF-kappaB is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NF-kappaB nuclear translocation and transcriptional activity, accompanied by IkappaB-alpha phosphorylation and degradation. Consistently, myotrophin-induced NF-kappaB activation was enhanced by wild-type IkappaB kinase (IKK) beta and abolished by the dominant-negative IKKbeta or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc) and also enhanced protein synthesis were partially inhibited by a potent NF-kappaB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominant-negative form of IkappaB-alpha or IKKbeta also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC-IKK-NF-kappaB pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

Deficiency of MicroRNA miR-1954 Promotes Cardiac Remodeling and Fibrosis.

Background Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II (AngII) has been implicated in the development of cardiac fibrosis. Recently, microRNAs have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of microRNAs in cardiac fibrosis remains unclear. Next-generation sequencing analysis identified a novel characterized microRNA, miR-1954, that was significantly reduced in AngII-infused mice. The finding led us to hypothesize that deficiency of miR-1954 triggers cardiac fibrosis. Methods and Results A transgenic mouse was created using α-MHC (α-myosin heavy chain) promoter and was challenged with AngII infusion. AngII induced cardiac hypertrophy and remodeling. The in vivo overexpression of miR-1954 showed significant reduction in cardiac mass and blood pressure in AngII-infused mice. Further analysis showed significant reduction in cardiac fibrotic genes, hypertrophy marker genes, and an inflammatory gene and restoration of a calcium-regulated gene (Atp2a2 [ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2]; also known as SERCA2), but no changes were observed in apoptotic genes. THBS1 (thrombospondin 1) is indicated as a target gene for miR-1954. Conclusions Our findings provide evidence, for the first time, that miR-1954 plays a critical role in cardiac fibrosis by targeting THBS1. We conclude that promoting the level of miR-1954 would be a promising strategy for the treatment of cardiac fibrosis.

The role of Thymosin ß4 in angiotensin II-induced cardiomyocytes growth.

INTRODUCTION: Thymosin beta-4 (Tß4) is an actin sequestering protein and is furthermore involved in diverse biological processes including cell proliferation, differentiation, wound healing, stem- or progenitor cell differentiation, and modulates inflammatory mediators. Tß4 also attenuates fibrosis. However, the role of Tß4 in cardiomyocytes hypertrophy is unknown. AREAS COVERED: In this review, we will discuss the role of Tß4 in cardiac remodeling that specifically includes cardiac hypertrophy and fibrosis only. Our review will further cover a new signaling pathway, the wingless and integrated-1 (Wnt) pathway in cardiac remodeling. In rat neonatal and adult cardiomyocytes stimulated with angiotensin II (Ang II), we showed that Tß4 has the ability to reduce cell sizes, attenuate hypertrophy marker genes expression, along with a panel of WNT-associated gene expressions induced by Ang II. Selected target gene WNT1-inducible-signaling pathway protein 1 (WISP-1) was identified by Tß4. Data further confirmed that WISP-1 overexpression promoted cardiomyocytes growth and was reversed by Tß4 pretreatment. EXPERT OPINION: Our data suggested that Tß4 protects cardiomyocytes from hypertrophic response by targeting WISP-1. The new role of Tß4 in cardiac hypertrophy advances our understanding, and the mechanism of action of Tß4 may provide a solid foundation for the treatment of cardiac disease.