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Papers by masum mia

Elements, Sep 22, 2021

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional chan... more Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

Elements, Sep 22, 2021

AIMS Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more AIMS Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodeling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signaling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response is not well established. METHODS AND RESULTS Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodeling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory program not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signaling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. CONCLUSIONS We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program. TRANSLATIONAL PERSPECTIVE Cardiac fibroblasts are the most prevalent cell type in the heart and play an important role in regulating post-myocardial infarction (MI) cardiac fibrosis. Excessive cardiac fibrosis causes ventricular stiffness leading to systolic/diastolic cardiac dysfunction and heart failure. Therefore, understanding the molecular mechanism of cardiac fibroblasts activation will help to modulate the post-MI fibrotic response and improve cardiac function. In our study, we show that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program.

Cardiovascular Research, Jun 16, 2021

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusion We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme.

Pulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung diseas... more Pulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung disease characterized by the scarring of lung due to excessive production of extracellular matrix (ECM). Recent studies have revealed the impact of macrophages in inflammation-induced fibrosis and distinct subsets of macrophages differentially contributes to the development of PF. However, the regulatory mechanisms and proinflammatory/profibrotc behaviour of heterogeneous population of lung macrophages during fibrogenesis remain incompletely understood. Here, we demonstrate the macrophage-specific role of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the development of bleomycin-induced inflammation and PF in mice. Both YAP/TAZ are activated in lung macrophages of fibrotic patients and of mice after bleomycin-induced injury. Myeloid-specific genetic deletion ofYap/Tazresulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs)...

Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a chara... more Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFb1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF-jB) pathway by phosphorylating IjB with the enzyme IjB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activa-tion of the NF-jB pathway. It is not known whether ACHP has potential anti-fibrotic properties. Using adult human dermal and lung fibrob-lasts we have investigated whether ACHP has the ability to inhibit the TGFb1-induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The p...

One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFb). TGFb is invol... more One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFb). TGFb is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1b (IL1b) can influence the severity of fibrosis, however much less is known about the direct effects on fibroblasts. Using lung and dermal fibroblasts, we have investigated the effects of IL1b, TGFb1, and IL1b in combination with TGFb1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase), and matrix metalloproteinases (MMPs). We found that IL1b alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1b is able to inhibit the TGFb1-induced myofibroblast formation as well as collagen synthesis. Glioma-associated oncogene homolog 1 (GLI1), the Hedgehog transcription factor that is involved in the transformation of fibroblasts into myofibrobla...

Developmental biology, Oct 24, 2016

The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact wit... more The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

Journal of Cellular and Molecular Medicine, 2015

Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a chara... more Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFb1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF-jB) pathway by phosphorylating IjB with the enzyme IjB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF-jB pathway. It is not known whether ACHP has potential anti-fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFb1-induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha-smooth muscle actin (aSMA) and SM22a, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post-treatment with ACHP partly reversed the expression of aSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen-modifying enzymes lysyl hydroxylase (PLOD1, PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF-jB pathway plays an important role in myofibroblast biology.

Cell and Tissue Research, 2015

Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the form... more Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the formation of myofibroblasts and the subsequent collagen deposition by these cells. Transforming growth factor beta1 (TGFβ1) plays a major role in the formation of myofibroblasts, e.g. by activating fibroblasts. Currently, no treatments are available to circumvent fibrosis. Caffeic acid phenethyl ester (CAPE) shows a broad spectrum of biological activities, including anti-fibrotic properties in vivo in mice and rats. However, little is known about the direct effects of CAPE on fibroblasts. We have tested whether CAPE is able to suppress myofibroblast formation and collagen formation of human dermal and lung fibroblasts exposed to TGFβ1, and found that this was indeed the case. In fact, the formation of myofibroblasts by TGFβ1 and subsequent collagen formation was completely abolished by CAPE. The same was observed for fibronectin and tenascin C. The lack of myofibroblast formation is likely due to the suppression of GLI1 and GLI2 expression by CAPE because of diminished nuclear SMAD2/3 levels. Posttreatment with CAPE after myofibroblast formation even resulted in a partial reversal of myofibroblasts into fibroblasts and/or reduction in collagen formation. Major discrepancies

Journal of Stem Cell Research & Therapy, 2015

Fibrose behelst het verlittekenen van weefsels en organen. Daardoor kunnen vitale functies uitval... more Fibrose behelst het verlittekenen van weefsels en organen. Daardoor kunnen vitale functies uitvallen, met de dood tot gevolg. Fibrose is in veel gevallen dan ook een zeer ernstige aandoening. Toch bestaat er geen enkel effectief medicijn tegen. Het kenmerk van fibrose is de excessieve productie van collageen door myofibroblasten. Deze myofibroblasten onstaan over het algemeen uit fibroblasten, doordat laatstgenoemde cellen worden blootgesteld aan bepaalde activatoren, zoals TGFβ. In celkweken kunnen deze omstandigheden in het laboratorium nagebootst worden. Hoewel we veel weten hoe fibroblasten worden omgezet naar myofibroblasten, zijn er grote vraagtekens of het mogelijk is om myofibroblasten weer terug te brengen naar hun normale voorlopercel. Als dit laatste inderdaad mogelijk is, dan zou dat een veelbelovende benadering kunnen zijn om fibrose te behandelen, zelfs als het in een vergevorderd stadium is (en er dus veel myofibroblasten zijn). Wij hebben een tweetal laagmoleculaire ...

Nature Communications

Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fi... more Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially m...

Cells

Fibrosis results from defective wound healing processes often seen after chronic injury and/or in... more Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by pathological myofibroblasts and myofibroblast-like cells. The Hippo signaling pathway is an evolutionarily conserved kinase cascade, which has been described well for its crucial role in cell proliferation, apoptosis, cell fate decisions, and stem cell self-renewal during development, homeostasis, and tissue regeneration. Recent investigations in clinical and pre-clinical models has shown that the Hippo signaling pathway is linked to the pathophysiology of fibrotic diseases in many organs including the lung, heart, liver, kidney, and skin. In this review, we have summarized recent evidences related to the contribution of the Hippo signaling pathway in the development of organ fibro...

The FEBS Journal, 2022

Inflammation is an evolutionarily conserved process and part of the body's defense mechanism.... more Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury- and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.

Cardiovascular Research, 2021

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response...

p-Anisaldehyde (1) and β-sitosterol were isolated from carbon tetrachloride and chloroform solubl... more p-Anisaldehyde (1) and β-sitosterol were isolated from carbon tetrachloride and chloroform soluble portion of the methanol extract of stem bark of Averrhoa carambola. The structures of the isolated compounds were elucidated by spectroscopic studies and by comparison with published data. Different partitionates of the methanol extract exhibited significant antimicrobial activities and varying degrees of cytotoxicity. Averrhoa carambola (Bengali name- Kamranga; Family, Oxalidaceae) is medium sized tree. It is planted in all over the Bangladesh.1 Fruits and its fruit juice are used as antioxidant, astringent, tonic also to treat diarrhoea, vomiting, dysentery, hepatic colic, bleeding piles, relieving thirst and febrile excitement. The leaves are antipruritic, antipyretic and anthelmintic and are also useful in scabies, fractured bones, and various types of poisoning, intermittent fevers and intestinal worms.2 Previous phytochemical investigation led to the isolation of

PLOS Biology, 2020

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional chan... more Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammato...

Frontiers in Cell and Developmental Biology, 2019

Heart disease continues to be the leading cause of morbidity and mortality worldwide. Cardiac mal... more Heart disease continues to be the leading cause of morbidity and mortality worldwide. Cardiac malformation during development could lead to embryonic or postnatal death. However, matured heart tissue has a very limited regenerative capacity. Thus, loss of cardiomyocytes from injury or diseases in adults could lead to heart failure. The Hippo signaling pathway is a newly identified signaling cascade that modulates regenerative response by regulating cardiomyocyte proliferation in the embryonic heart, as well as in postnatal hearts after injury. In this review, we summarize recent findings highlighting the function and regulation of the Hippo signaling pathway in cardiac development and diseases.

eLife, 2019

Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating nu... more Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs), and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-β-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positi...

Elements, Sep 22, 2021

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional chan... more Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

Elements, Sep 22, 2021

AIMS Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more AIMS Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodeling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signaling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response is not well established. METHODS AND RESULTS Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodeling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory program not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signaling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. CONCLUSIONS We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program. TRANSLATIONAL PERSPECTIVE Cardiac fibroblasts are the most prevalent cell type in the heart and play an important role in regulating post-myocardial infarction (MI) cardiac fibrosis. Excessive cardiac fibrosis causes ventricular stiffness leading to systolic/diastolic cardiac dysfunction and heart failure. Therefore, understanding the molecular mechanism of cardiac fibroblasts activation will help to modulate the post-MI fibrotic response and improve cardiac function. In our study, we show that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory program.

Cardiovascular Research, Jun 16, 2021

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusion We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme.

Pulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung diseas... more Pulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung disease characterized by the scarring of lung due to excessive production of extracellular matrix (ECM). Recent studies have revealed the impact of macrophages in inflammation-induced fibrosis and distinct subsets of macrophages differentially contributes to the development of PF. However, the regulatory mechanisms and proinflammatory/profibrotc behaviour of heterogeneous population of lung macrophages during fibrogenesis remain incompletely understood. Here, we demonstrate the macrophage-specific role of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the development of bleomycin-induced inflammation and PF in mice. Both YAP/TAZ are activated in lung macrophages of fibrotic patients and of mice after bleomycin-induced injury. Myeloid-specific genetic deletion ofYap/Tazresulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs)...

Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a chara... more Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFb1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF-jB) pathway by phosphorylating IjB with the enzyme IjB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activa-tion of the NF-jB pathway. It is not known whether ACHP has potential anti-fibrotic properties. Using adult human dermal and lung fibrob-lasts we have investigated whether ACHP has the ability to inhibit the TGFb1-induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The p...

One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFb). TGFb is invol... more One of the most potent pro-fibrotic cytokines is transforming growth factor (TGFb). TGFb is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1b (IL1b) can influence the severity of fibrosis, however much less is known about the direct effects on fibroblasts. Using lung and dermal fibroblasts, we have investigated the effects of IL1b, TGFb1, and IL1b in combination with TGFb1 on myofibroblast formation, collagen synthesis and collagen modification (including prolyl hydroxylase, lysyl hydroxylase and lysyl oxidase), and matrix metalloproteinases (MMPs). We found that IL1b alone has no obvious pro-fibrotic effect on fibroblasts. However, IL1b is able to inhibit the TGFb1-induced myofibroblast formation as well as collagen synthesis. Glioma-associated oncogene homolog 1 (GLI1), the Hedgehog transcription factor that is involved in the transformation of fibroblasts into myofibrobla...

Developmental biology, Oct 24, 2016

The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact wit... more The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

Journal of Cellular and Molecular Medicine, 2015

Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a chara... more Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFb1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF-jB) pathway by phosphorylating IjB with the enzyme IjB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF-jB pathway. It is not known whether ACHP has potential anti-fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFb1-induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha-smooth muscle actin (aSMA) and SM22a, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post-treatment with ACHP partly reversed the expression of aSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen-modifying enzymes lysyl hydroxylase (PLOD1, PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF-jB pathway plays an important role in myofibroblast biology.

Cell and Tissue Research, 2015

Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the form... more Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the formation of myofibroblasts and the subsequent collagen deposition by these cells. Transforming growth factor beta1 (TGFβ1) plays a major role in the formation of myofibroblasts, e.g. by activating fibroblasts. Currently, no treatments are available to circumvent fibrosis. Caffeic acid phenethyl ester (CAPE) shows a broad spectrum of biological activities, including anti-fibrotic properties in vivo in mice and rats. However, little is known about the direct effects of CAPE on fibroblasts. We have tested whether CAPE is able to suppress myofibroblast formation and collagen formation of human dermal and lung fibroblasts exposed to TGFβ1, and found that this was indeed the case. In fact, the formation of myofibroblasts by TGFβ1 and subsequent collagen formation was completely abolished by CAPE. The same was observed for fibronectin and tenascin C. The lack of myofibroblast formation is likely due to the suppression of GLI1 and GLI2 expression by CAPE because of diminished nuclear SMAD2/3 levels. Posttreatment with CAPE after myofibroblast formation even resulted in a partial reversal of myofibroblasts into fibroblasts and/or reduction in collagen formation. Major discrepancies

Journal of Stem Cell Research & Therapy, 2015

Fibrose behelst het verlittekenen van weefsels en organen. Daardoor kunnen vitale functies uitval... more Fibrose behelst het verlittekenen van weefsels en organen. Daardoor kunnen vitale functies uitvallen, met de dood tot gevolg. Fibrose is in veel gevallen dan ook een zeer ernstige aandoening. Toch bestaat er geen enkel effectief medicijn tegen. Het kenmerk van fibrose is de excessieve productie van collageen door myofibroblasten. Deze myofibroblasten onstaan over het algemeen uit fibroblasten, doordat laatstgenoemde cellen worden blootgesteld aan bepaalde activatoren, zoals TGFβ. In celkweken kunnen deze omstandigheden in het laboratorium nagebootst worden. Hoewel we veel weten hoe fibroblasten worden omgezet naar myofibroblasten, zijn er grote vraagtekens of het mogelijk is om myofibroblasten weer terug te brengen naar hun normale voorlopercel. Als dit laatste inderdaad mogelijk is, dan zou dat een veelbelovende benadering kunnen zijn om fibrose te behandelen, zelfs als het in een vergevorderd stadium is (en er dus veel myofibroblasten zijn). Wij hebben een tweetal laagmoleculaire ...

Nature Communications

Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fi... more Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially m...

Cells

Fibrosis results from defective wound healing processes often seen after chronic injury and/or in... more Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by pathological myofibroblasts and myofibroblast-like cells. The Hippo signaling pathway is an evolutionarily conserved kinase cascade, which has been described well for its crucial role in cell proliferation, apoptosis, cell fate decisions, and stem cell self-renewal during development, homeostasis, and tissue regeneration. Recent investigations in clinical and pre-clinical models has shown that the Hippo signaling pathway is linked to the pathophysiology of fibrotic diseases in many organs including the lung, heart, liver, kidney, and skin. In this review, we have summarized recent evidences related to the contribution of the Hippo signaling pathway in the development of organ fibro...

The FEBS Journal, 2022

Inflammation is an evolutionarily conserved process and part of the body's defense mechanism.... more Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury- and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.

Cardiovascular Research, 2021

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarct... more Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response...

p-Anisaldehyde (1) and β-sitosterol were isolated from carbon tetrachloride and chloroform solubl... more p-Anisaldehyde (1) and β-sitosterol were isolated from carbon tetrachloride and chloroform soluble portion of the methanol extract of stem bark of Averrhoa carambola. The structures of the isolated compounds were elucidated by spectroscopic studies and by comparison with published data. Different partitionates of the methanol extract exhibited significant antimicrobial activities and varying degrees of cytotoxicity. Averrhoa carambola (Bengali name- Kamranga; Family, Oxalidaceae) is medium sized tree. It is planted in all over the Bangladesh.1 Fruits and its fruit juice are used as antioxidant, astringent, tonic also to treat diarrhoea, vomiting, dysentery, hepatic colic, bleeding piles, relieving thirst and febrile excitement. The leaves are antipruritic, antipyretic and anthelmintic and are also useful in scabies, fractured bones, and various types of poisoning, intermittent fevers and intestinal worms.2 Previous phytochemical investigation led to the isolation of

PLOS Biology, 2020

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional chan... more Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammato...

Frontiers in Cell and Developmental Biology, 2019

Heart disease continues to be the leading cause of morbidity and mortality worldwide. Cardiac mal... more Heart disease continues to be the leading cause of morbidity and mortality worldwide. Cardiac malformation during development could lead to embryonic or postnatal death. However, matured heart tissue has a very limited regenerative capacity. Thus, loss of cardiomyocytes from injury or diseases in adults could lead to heart failure. The Hippo signaling pathway is a newly identified signaling cascade that modulates regenerative response by regulating cardiomyocyte proliferation in the embryonic heart, as well as in postnatal hearts after injury. In this review, we summarize recent findings highlighting the function and regulation of the Hippo signaling pathway in cardiac development and diseases.

eLife, 2019

Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating nu... more Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs), and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-β-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positi...