Case Cardiovascular Research Institute

Cleveland, OH, United States

Case Cardiovascular Research Institute

Cleveland, OH, United States
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Prosdocimo D.A.,Case Cardiovascular Research Institute | Prosdocimo D.A.,Harrington Heart and Vascular Institute | Prosdocimo D.A.,University Hospitals Case Medical Center | Prosdocimo D.A.,Case Western Reserve University | And 8 more authors.
Trends in Cardiovascular Medicine | Year: 2015

Kruppel-like factors (KLF) are zinc-finger DNA-binding transcription factors that are critical regulators of tissue homeostasis. Emerging evidence suggests that KLFs are critical regulators of muscle biology in the context of cardiovascular health and disease. The focus of this review is to provide an overview of the current state of knowledge regarding the physiologic and pathologic roles of KLFs in the three lineages of muscle: cardiac, smooth, and skeletal. © 2015 Elsevier Inc.

Cuttano R.,the FIRC Institute of Molecular Oncology | Rudini N.,the FIRC Institute of Molecular Oncology | Bravi L.,the FIRC Institute of Molecular Oncology | Corada M.,the FIRC Institute of Molecular Oncology | And 21 more authors.
EMBO Molecular Medicine | Year: 2016

Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5-MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM. Synopsis: Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target. KLF4 is strongly upregulated in endothelial cells in the absence of any of the three CCM genes. The endothelial-to-mesenchymal transition observed in endothelial cells null for CCM1 is induced by KLF4. KLF4 activates TGFβ/BMP signaling by increasing Bmp6 expression in endothelial cells in the absence of CCM1. The development and progression of cavernomas is strongly reduced upon genetic Klf4 inactivation. KLF4 is a strong candidate as a novel target for the pharmacological treatment of CCM, since its inactivation reduces mouse mortality associated to this disease by 75%. Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target. © 2016 EMBO.

Nayak L.,Case Cardiovascular Research Institute | Nayak L.,Case Western Reserve University | Goduni L.,Case Cardiovascular Research Institute | Takami Y.,Case Cardiovascular Research Institute | And 4 more authors.
American Journal of Pathology | Year: 2013

Although myeloid cell activation is requisite for an optimal innate immune response, this process must be tightly controlled to prevent collateral host tissue damage. Kruppel-like factor 2 (KLF2) is a potent regulator of myeloid cell proinflammatory activation. As an approximately 30% to 50% reduction in KLF2 levels has been observed in human subjects with acute or chronic inflammatory disorders, we studied the biological response to inflammation in KLF2+/- mice. Herein, we show that partial deficiency of KLF2 modulates the in vivo response to acute (sepsis) and subacute (skin) inflammatory challenge. Mechanistically, we link the anti-inflammatory effects of KLF2 to the inhibition of NF-κB transcriptional activity. Collectively, the observations provide biologically relevant insights into KLF2-mediated modulation of these inflammatory processes that could potentially be manipulated for therapeutic gain. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Mahabeleshwar G.,Case Cardiovascular Research Institute | Kawanami D.,Case Cardiovascular Research Institute | Sharma N.,Case Cardiovascular Research Institute | Takami Y.,Case Cardiovascular Research Institute | And 15 more authors.
Immunity | Year: 2011

Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system. © 2011 Elsevier Inc.

Zhang L.,Case Cardiovascular Research Institute | Zhang L.,Case Western Reserve University | Prosdocimo D.A.,Case Cardiovascular Research Institute | Bai X.,Case Western Reserve University | And 6 more authors.
Cell Reports | Year: 2015

Circadian rhythms offer temporal control of anticipatory physiologic adaptations in animals. In the mammalian cardiovascular system, the importance of these rhythms is underscored by increased cardiovascular disease in shift workers, findings recapitulated in experimental animal models. However, a nodal regulator that allows integration of central and peripheral information and coordinates cardiac rhythmic output has been elusive. Here, we show that kruppel-like factor 15 (KLF15) governs a biphasic transcriptomic oscillation in the heart with a maximum ATP production phase and a remodeling and repair phase corresponding to the active and resting phase of a rodent. Depletion of KLF15 in cardiomyocytes leads to a disorganized oscillatory behavior without phasic partition despite an intact core clock. Thus, KLF15 is a nodal connection between the clock and meaningful rhythmicity in the heart. © 2015 The Authors.

Prosdocimo D.A.,Case Cardiovascular Research Institute | Prosdocimo D.A.,Case Western Reserve University | John J.E.,Case Cardiovascular Research Institute | John J.E.,Case Western Reserve University | And 10 more authors.
PPAR Research | Year: 2015

The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism. © 2015 Domenick A. Prosdocimo et al.

Liao X.,Case Cardiovascular Research Institute | Haldar S.M.,Case Cardiovascular Research Institute | Lu Y.,Case Cardiovascular Research Institute | Jeyaraj D.,Case Cardiovascular Research Institute | And 5 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2010

Krüppel-like factors (KLF) are a subfamily of the zinc-finger class of transcriptional regulators that play important roles in diverse cellular processes. While a number of KLFs are expressed in cardiomyocytes, little is known about their specific roles in the heart in vivo. Here, we demonstrate that KLF4 is induced by hypertrophic stimuli in cultured cardiomyocytes and in the mouse heart. Overexpression of KLF4 in neonatal rat ventricular myocytes inhibits three cardinal features of cardiomyocyte hypertrophy: fetal gene expression, protein synthesis, and cell enlargement. Conversely, mice with cardiomyocyte-specific deletion of KLF4 (CM-K4KO) are highly sensitized to transverse aortic constriction (TAC) and exhibit high rates of mortality. CM-K4KO mice that survive TAC display severe pathologic cardiac hypertrophy characterized by increased cardiac mass, depressed LV systolic function, pulmonary congestion, cavity dilation and attenuated LV wall thickening when compared to control genotypes. In addition, CM-K4KO mice develop increased myocardial fibrosis and apoptotic cell death after TAC. Collectively, these studies implicate KLF4 as a novel transcriptional regulator that is indispensible for the heart's response to stress in vivo. © 2010 Elsevier Ltd.

Date D.,Case Cardiovascular Research Institute | Das R.,Cleveland Clinic | Narla G.,Case Western Reserve University | Simon D.I.,Case Cardiovascular Research Institute | And 2 more authors.
Journal of Biological Chemistry | Year: 2014

Accumulating evidence supports the importance of macrophage plasticity in a broad spectrum of biological processes operative in health and disease. A major locus of control regulating macrophage polarization is at the transcriptional level, and several major pathways have been elucidated in recent years. In this study, we identify the Kruppel-like transcription factor 6 (KLF6) as a molecular toggle controlling macrophage speciation. KLF6 expression was robustly induced by pro-inflammatory M1 stimuli (e.g. LPS and IFN-γ) and strongly suppressed by M2 stimuli (e.g. IL4 and IL-13) in human and murine macrophages. Gain- and loss-of-function studies suggest that KLF6 is required for optimal LPS-induced pro-inflammatory gene expression, acting cooperatively with NF-κB. Furthermore, KLF6 inhibits anti-inflammatory gene expression by negatively regulating peroxisome proliferator-activated receptor γ expression in macrophages. Collectively, these observations identify KLF6 as a novel transcriptional regulator of macrophage polarization. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Mata M.F.,University of Lisbon | Lopes J.P.,Case Cardiovascular Research Institute | Ishikawa M.,Case Cardiovascular Research Institute | Alaiti M.A.,Case Cardiovascular Research Institute | And 3 more authors.
Cytotherapy | Year: 2015

Background aims: The therapeutic application of CD34+ circulating progenitor cells (which includes endothelial progenitor cells) has been hampered by the quantity and quality of isolated circulating CD34+ cells from the patient's peripheral blood. Our group had previously established a suspension culture system for human CD34+ cells, with increased quantity and quality (QQ) of the angiogenic cell product. We successfully scaled up the expansion process with the use of culture bags because there is the need to move toward a dynamic and fully controlled bioreactor system to meet Good Manufacturing Practice (GMP) standards and attain clinically meaningful cell doses in a time- and cost-effective way. Methods: CD34+ cells isolated from mobilized peripheral blood of healthy donors were expanded ex vivo for 7 days in QQ medium (serum-free) in cell culture bags (30 mL) and pre- and post-expansion cells were characterized by means of flow cytometry and quantitative polymerase chain reaction; angiogenic potential was assessed by use of the in vitro tube formation assay. Results: Our data show effective expansion of the cultured population (7-fold) while maintaining the stem/progenitor content and increasing the endothelial population. Moreover, post-expanded cells showed higher tube formation capacity compared with pre-expanded cells. In addition, an upregulation of the anti-inflammatory gene expression and a downregulation of pro-inflammatory genes were observed, which suggests that the increase in angiogenic potential is not paired with an increase in the inflammatory profile. Conclusions: The QQ expansion method was successfully scaled up to cell culture bags and was able to meet GMP standards, with a higher in vitro angiogenic profile. © 2015 International Society for Cellular Therapy.

Shi H.,Case Cardiovascular Research Institute | Sheng B.,Case Cardiovascular Research Institute | Zhang C.,Case Cardiovascular Research Institute | Nayak L.,Case Western Reserve University | And 3 more authors.
Journal of Neuroimmunology | Year: 2014

Cells of the innate immune system are important mediators of multiple sclerosis (MS). We have previously identified Kruppel-like factor 2 (KLF2) as a critical negative regulator of myeloid activation in the setting of bacterial infection and sepsis, but the role of myeloid KLF2 in MS has not been investigated. In this study, myeloid KLF2 deficient mice exhibited more severe neurological dysfunction and increased spinal cord demyelination and neuroinflammation in experimental autoimmune encephalomyelitis. This study represents the first description of a significant role of myeloid KLF2 in neuroinflammation, identifying KLF2 as a potential target for further investigation in patients with MS. © 2014 Elsevier B.V.

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