Akm Wara - Academia.edu (original) (raw)

Papers by Akm Wara

Circulation

Introduction: Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) exhibit unique miRN... more Introduction: Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) exhibit unique miRNA profiles, which regulate their overall function. However, whether differentially expressed miRNAs can be used for transcriptional reprogramming of SMCs into ECs is unknown. MiRNA profiling of SMCs and ECs revealed differential regulation of miR-143-3p, miR-145-3p, miR-146a-5p, and miR-181b-5p as a set of candidates for transdifferentiation. Methods: Human coronary SMCs were transfected with miR-143-3p and miR-145-3p inhibitors alongside miR-146a-5p and miR-181b-5p mimics and selectively expanded. Induced endothelial cells (iECs) were then assessed for their transcriptional, protein expression, and functional similarities to ECs (Fig. 1). Results: Principal component and gene set enrichment analyses determined that iECs are transcriptionally clustered closer to ECs than SMCs in whole transcriptome profiling and selected EC and SMC gene sets. Top pathways included ‘blood vessel morphogen...

Circulation Research

Background: Perivascular fibrosis, characterized by increased amount of connective tissue around ... more Background: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Methods: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient ( Klf10 fl/fl CD4 Cre+ ; [TKO]) and CD4-Cre ( Klf10 +/+ CD4 Cre+ ; [Cre]) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. Results: TF profiling identified increased KLF10 expression in hypertensive human...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2021

Objective: Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optim... more Objective: Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optimal medical therapies. This study aimed to identify evolutionarily conserved lesion-based regulatory signaling networks in diabetic versus nondiabetic conditions during the development of atherosclerosis in an initial translational effort to provide insights for targets. Approach and Results: Serial 3-mm coronary artery segments of hypercholesterolemic Yorkshire swine and diabetic-hypercholesterolemic swine were characterized as mild, moderate, or severe phenotypic manifestations of coronary atherosclerosis based on histopathologic examination. Lesional RNA sequencing was performed (n=3–8 lesions per group) corresponding to increasing phenotypic severity. Differentially expressed genes, transcription factors, upstream regulators, and hubs were validated using the NanoString technology and a human atherosclerotic specimen cohort. Despite similar stage histopathologic characterization of le...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2021

Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development... more Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and Results: We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr −/− mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-β1 (transform...

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Sep 1, 2016

Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell... more Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-κB signaling in response to TNF-α. Here, we demonstrate that miR-181b uniquely inhibits upstream NF-κB signaling in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-κB signaling, demonstrated by reduction of phospho-IKK-β, -IκB-α, and p65 nuclear translocation in ECs. MiR-181b also reduced expression of NF-κB target genes VCAM-1, intercellular adhesion molecule-1, E-selectin, and tissue factor. Mechanistically, miR-181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease-activa...

Journal of molecular and cellular cardiology, Jan 9, 2016

Wound healing is a physiological reparative response to injury and a well-orchestrated process th... more Wound healing is a physiological reparative response to injury and a well-orchestrated process that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix deposition, and wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. Herein, we investigate the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to high glucose in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~3.5-fold) four days post-wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to ~80%), increased granulation tissue thickness (by 2.5-fold) and accelerated wound clo...

Circulation

Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue aroun... more Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Angiotensin II (Ang II) contributes to vascular disease via promoting T-cell activation and end-organ damage. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Objective: Kruppel-like Factor 10 is a transcription factor expressed in T cell subsets. We sought to investigate the role of KLF10 in CD4+ T cells in regulating vascular damage in an AngII mouse model. Methods: CD4-targeted KLF10 deficient (TKO) and CD4-Cre (WT) mice were generated and subjected to 28 days of Ang II infusion. Endpoint characterization included fibrotic organ transcriptomic analysis, multi-organ histology, flow cytometry, cytokine analysis, myograph vasoreactivity, and cardiac echocardiography. Results: TKO mice showed enhanced perivascular fibrosis compared to WT mice by hi...

Circulation, 2006

Background: Recent studies have shown a critical role for CD4+ CD25+ T regulatory cells for inhib... more Background: Recent studies have shown a critical role for CD4+ CD25+ T regulatory cells for inhibiting the progression of atherosclerosis in mice, an effect dependent in part on TGF-beta signaling....

The Nihon University journal of medicine, 2003

Smooth muscle cell (SMC) migration and proliferation are key events in the arterial response to i... more Smooth muscle cell (SMC) migration and proliferation are key events in the arterial response to injury, vessel development and atherogenesis. We have demonstrated that elastase expression is associated with SMC migration and proliferation following arterial injury. To clarify the mechanism of the effects of elastase during SMC migration and proliferation and to develop a new treatment for atherogenesis, an elastase inhibitor was administered to rats at 2 hours before balloon injury and once every day thereafter. The elastase inhibitor significantly reduced the intima area, cell number and labelling index as compared to the corresponding values for control rats at 10 days after balloon injury, although at 5 days after the injury, the intima area, cell number, and labelling index were the same in the controls and elastase inhibitor-treated rats. Treatment with the elastase inhibitor exerted no effect on the media area, cell number or labelling index at 5 or 10 days after the balloon i...

Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medica... more Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430022, and; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Division, Vanderbilt University School of Medicine, Nashville, TN 37232.

A dipose tissue dysfunction, characterized by low-grade inflammation, is considered to play a pri... more A dipose tissue dysfunction, characterized by low-grade inflammation, is considered to play a primary role in obesityassociated insulin resistance, which predisposes the majority of obese patients to the development of important chronic metabolic diseases including, type 2 diabetes mellitus and cardiovascular diseases. 1-4 Excessive caloric intake may expose tissues such as white adipose tissue to superphysiological levels of metabolic substrates and promote the development of low-grade inflammation. 5 Inflamed white adipose tissue contains a range of leukocyte subsets including monocytes that preferentially differentiate toward M1 macrophages, and they are associated with increased expression Molecular Medicine

Objective: Thrombogenic and inflammatory mediators such as thrombin induce NF-kB-mediated EC acti... more Objective: Thrombogenic and inflammatory mediators such as thrombin induce NF-kB-mediated EC activation and dysfunction, which contribute to the pathogenesis of arterial thrombosis. The role of the anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Methods and Results: It has been demonstrated that miR-181b inhibits downstream NF-kB signaling in response to TNF-a. Herein, we reveal that miR-181b can inhibit upstream NF-kB signaling uniquely in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-kB signaling demonstrated by the reduction of phospho-IKK-b, -IkB-a, and p65 nuclear translocation in ECs. MiR-181b also reduced the expression of NF-kB target genes VCAM-1, ICAM-1, E-selectin, PAI-1, and tissue factor. Mechanistically, miR-181b targets Card10, an adaptor protein that participates in the activation of the IKK complex in response to signals transduced from G-protein coupled receptors such as PAR-1. MiR-181b reduce...

Ethology and Sociobiology, 1992

... to ResourceAccess and Parental Age in a Small Norwegian Farming Parish During the Period 1700... more ... to ResourceAccess and Parental Age in a Small Norwegian Farming Parish During the Period 17001900 0 Eivin ROskaft, Annelise Wara, and ... it has previously been argued that both fertility and the reproductive value of females are age dependent factors (eg , Williams 1975) In ...

Circulation

Introduction: Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) exhibit unique miRN... more Introduction: Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) exhibit unique miRNA profiles, which regulate their overall function. However, whether differentially expressed miRNAs can be used for transcriptional reprogramming of SMCs into ECs is unknown. MiRNA profiling of SMCs and ECs revealed differential regulation of miR-143-3p, miR-145-3p, miR-146a-5p, and miR-181b-5p as a set of candidates for transdifferentiation. Methods: Human coronary SMCs were transfected with miR-143-3p and miR-145-3p inhibitors alongside miR-146a-5p and miR-181b-5p mimics and selectively expanded. Induced endothelial cells (iECs) were then assessed for their transcriptional, protein expression, and functional similarities to ECs (Fig. 1). Results: Principal component and gene set enrichment analyses determined that iECs are transcriptionally clustered closer to ECs than SMCs in whole transcriptome profiling and selected EC and SMC gene sets. Top pathways included ‘blood vessel morphogen...

Circulation Research

Background: Perivascular fibrosis, characterized by increased amount of connective tissue around ... more Background: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Methods: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient ( Klf10 fl/fl CD4 Cre+ ; [TKO]) and CD4-Cre ( Klf10 +/+ CD4 Cre+ ; [Cre]) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. Results: TF profiling identified increased KLF10 expression in hypertensive human...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2021

Objective: Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optim... more Objective: Accelerated atherosclerosis in diabetes constitutes an ongoing challenge despite optimal medical therapies. This study aimed to identify evolutionarily conserved lesion-based regulatory signaling networks in diabetic versus nondiabetic conditions during the development of atherosclerosis in an initial translational effort to provide insights for targets. Approach and Results: Serial 3-mm coronary artery segments of hypercholesterolemic Yorkshire swine and diabetic-hypercholesterolemic swine were characterized as mild, moderate, or severe phenotypic manifestations of coronary atherosclerosis based on histopathologic examination. Lesional RNA sequencing was performed (n=3–8 lesions per group) corresponding to increasing phenotypic severity. Differentially expressed genes, transcription factors, upstream regulators, and hubs were validated using the NanoString technology and a human atherosclerotic specimen cohort. Despite similar stage histopathologic characterization of le...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2021

Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development... more Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and Results: We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr −/− mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-β1 (transform...

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Sep 1, 2016

Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell... more Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-κB signaling in response to TNF-α. Here, we demonstrate that miR-181b uniquely inhibits upstream NF-κB signaling in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-κB signaling, demonstrated by reduction of phospho-IKK-β, -IκB-α, and p65 nuclear translocation in ECs. MiR-181b also reduced expression of NF-κB target genes VCAM-1, intercellular adhesion molecule-1, E-selectin, and tissue factor. Mechanistically, miR-181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease-activa...

Journal of molecular and cellular cardiology, Jan 9, 2016

Wound healing is a physiological reparative response to injury and a well-orchestrated process th... more Wound healing is a physiological reparative response to injury and a well-orchestrated process that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix deposition, and wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. Herein, we investigate the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to high glucose in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~3.5-fold) four days post-wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to ~80%), increased granulation tissue thickness (by 2.5-fold) and accelerated wound clo...

Circulation

Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue aroun... more Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Angiotensin II (Ang II) contributes to vascular disease via promoting T-cell activation and end-organ damage. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Objective: Kruppel-like Factor 10 is a transcription factor expressed in T cell subsets. We sought to investigate the role of KLF10 in CD4+ T cells in regulating vascular damage in an AngII mouse model. Methods: CD4-targeted KLF10 deficient (TKO) and CD4-Cre (WT) mice were generated and subjected to 28 days of Ang II infusion. Endpoint characterization included fibrotic organ transcriptomic analysis, multi-organ histology, flow cytometry, cytokine analysis, myograph vasoreactivity, and cardiac echocardiography. Results: TKO mice showed enhanced perivascular fibrosis compared to WT mice by hi...

Circulation, 2006

Background: Recent studies have shown a critical role for CD4+ CD25+ T regulatory cells for inhib... more Background: Recent studies have shown a critical role for CD4+ CD25+ T regulatory cells for inhibiting the progression of atherosclerosis in mice, an effect dependent in part on TGF-beta signaling....

The Nihon University journal of medicine, 2003

Smooth muscle cell (SMC) migration and proliferation are key events in the arterial response to i... more Smooth muscle cell (SMC) migration and proliferation are key events in the arterial response to injury, vessel development and atherogenesis. We have demonstrated that elastase expression is associated with SMC migration and proliferation following arterial injury. To clarify the mechanism of the effects of elastase during SMC migration and proliferation and to develop a new treatment for atherogenesis, an elastase inhibitor was administered to rats at 2 hours before balloon injury and once every day thereafter. The elastase inhibitor significantly reduced the intima area, cell number and labelling index as compared to the corresponding values for control rats at 10 days after balloon injury, although at 5 days after the injury, the intima area, cell number, and labelling index were the same in the controls and elastase inhibitor-treated rats. Treatment with the elastase inhibitor exerted no effect on the media area, cell number or labelling index at 5 or 10 days after the balloon i...

Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medica... more Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 430022, and; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Division, Vanderbilt University School of Medicine, Nashville, TN 37232.

A dipose tissue dysfunction, characterized by low-grade inflammation, is considered to play a pri... more A dipose tissue dysfunction, characterized by low-grade inflammation, is considered to play a primary role in obesityassociated insulin resistance, which predisposes the majority of obese patients to the development of important chronic metabolic diseases including, type 2 diabetes mellitus and cardiovascular diseases. 1-4 Excessive caloric intake may expose tissues such as white adipose tissue to superphysiological levels of metabolic substrates and promote the development of low-grade inflammation. 5 Inflamed white adipose tissue contains a range of leukocyte subsets including monocytes that preferentially differentiate toward M1 macrophages, and they are associated with increased expression Molecular Medicine

Objective: Thrombogenic and inflammatory mediators such as thrombin induce NF-kB-mediated EC acti... more Objective: Thrombogenic and inflammatory mediators such as thrombin induce NF-kB-mediated EC activation and dysfunction, which contribute to the pathogenesis of arterial thrombosis. The role of the anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Methods and Results: It has been demonstrated that miR-181b inhibits downstream NF-kB signaling in response to TNF-a. Herein, we reveal that miR-181b can inhibit upstream NF-kB signaling uniquely in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-kB signaling demonstrated by the reduction of phospho-IKK-b, -IkB-a, and p65 nuclear translocation in ECs. MiR-181b also reduced the expression of NF-kB target genes VCAM-1, ICAM-1, E-selectin, PAI-1, and tissue factor. Mechanistically, miR-181b targets Card10, an adaptor protein that participates in the activation of the IKK complex in response to signals transduced from G-protein coupled receptors such as PAR-1. MiR-181b reduce...

Ethology and Sociobiology, 1992

... to ResourceAccess and Parental Age in a Small Norwegian Farming Parish During the Period 1700... more ... to ResourceAccess and Parental Age in a Small Norwegian Farming Parish During the Period 17001900 0 Eivin ROskaft, Annelise Wara, and ... it has previously been argued that both fertility and the reproductive value of females are age dependent factors (eg , Williams 1975) In ...