Browsing by Author "Roy, Rajika"

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    A (Alpha1-Adrenergic Receptors), B (Blocking Alpha1-Adrenergic Receptors), C (Catecholamines): On the Road to Heart Failure
    (JACC: Basic to Translational Science, 2024-01-01) Roy, Rajika; Koch, Walter J
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    A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload
    (Journal of Molecular and Cellular Cardiology, 2021-05) Bledzka, Kamila M; Manaserh, Iyad H; Grondolsky, Jessica; Pfleger, Jessica; Roy, Rajika; Gao, Erhe; Chuprun, J Kurt; Koch, Walter J; Schumacher, Sarah M
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    A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure
    (Science Signaling, 2021-03-30) Coleman, Ryan C; Eguchi, Akito; Lieu, Melissa; Roy, Rajika; Barr, Eric W; Ibetti, Jessica; Lucchese, Anna-Maria; Peluzzo, Amanda M; Gresham, Kenneth; Chuprun, J Kurt; Koch, Walter J
    GRK5 does not mediate pathological signaling in the heart if its nuclear translocation is disrupted.
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    Adding another GRK to the fire of heart failure
    (European Heart Journal, 2021-04-07) Roy, Rajika; Koch, Walter J
    Abstract
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    Cardiac Myocyte‐Specific Overexpression of FASTKD1 Prevents Ventricular Rupture After Myocardial Infarction
    (Journal of the American Heart Association, 2023-02-21) Marshall, Kurt D; Klutho, Paula J; Song, Lihui; Roy, Rajika; Krenz, Maike; Baines, Christopher P
    Background The mitochondrial mRNA‐binding protein FASTKD1 (Fas‐activated serine/threonine [FAST] kinase domain–containing protein 1) protects myocytes from oxidative stress in vitro. However, the role of FASTKD1 in the myocardium in vivo is unknown. Therefore, we developed cardiac‐specific FASTKD1 transgenic mice to test the effects of this protein on experimental myocardial infarction (MI). Methods and Results Transgenic mouse lines with cardiac myocyte‐specific overexpression of FASTKD1 to varying degrees were generated. These mice displayed normal cardiac morphological features and function at the gross and microscopic levels. Isolated cardiac mitochondria from all transgenic mouse lines showed normal mitochondrial function, ATP levels, and permeability transition pore activity. Male nontransgenic and transgenic mice from the highest‐expressing line were subjected to 8 weeks of permanent coronary ligation. Of nontransgenic mice, 40% underwent left ventricular free wall rupture within 7 days of MI compared with 0% of FASTKD1‐overexpressing mice. At 3 days after MI, FASTKD1 overexpression did not alter infarct size. However, increased FASTKD1 resulted in decreased neutrophil and increased macrophage infiltration, elevated levels of the extracellular matrix component periostin, and enhanced antioxidant capacity compared with control mice. In contrast, markers of mitochondrial fusion/fission and apoptosis remained unaltered. Instead, transcriptomic analyses indicated activation of the integrated stress response in the FASTKD1 transgenic hearts. Conclusions Cardiac‐specific overexpression of FASTKD1 results in viable mice displaying normal cardiac morphological features and function. However, these mice are resistant to MI‐induced cardiac rupture and display altered inflammatory, extracellular matrix, and antioxidant responses following MI. Moreover, these protective effects were associated with enhanced activation of the integrated stress response.
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    Cardioprotection by placenta-derived stromal cells in a murine myocardial infarction model
    (Journal of Surgical Research, 2013-11) Roy, Rajika; Brodarac, Andreja; Kukucka, Marian; Kurtz, Andreas; Becher, Peter Moritz; Jülke, Kerstin; Choi, Yeong-Hoon; Pinzur, Lena; Chajut, Ayelet; Tschöpe, Carsten; Stamm, Christof
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    Characterization of βARKct engineered cellular extracellular vesicles and model specific cardioprotection
    (American Journal of Physiology-Heart and Circulatory Physiology, 2021-04-01) Kwon, Jin-Sook; Schumacher, Sarah M; Gao, Erhe; Chuprun, J Kurt; Ibetti, Jessica; Roy, Rajika; Khan, Mohsin; Kishore, Raj; Koch, Walter J
    βARKct, the peptide inhibitor of GRK2, improves survival and metabolic functions of cardiac-derived progenitor cells. As any benefit of stem cells in the ischemic and injured heart suggests paracrine mechanisms via secreted EVs, we investigated whether CDC-βARKct engineered EVs would show any benefit over control CDC-EVs. Compared with control EVs, βARKct-containing EVs displayed some unique beneficial properties that may be due to altered pro- and anti-inflammatory cytokines within the vesicles.
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    Decellularized amniotic membrane attenuates postinfarct left ventricular remodeling
    (Journal of Surgical Research, 2016-02) Roy, Rajika; Haase, Tobias; Ma, Nan; Bader, Andreas; Becker, Matthias; Seifert, Martina; Choi, Yeong-Hoon; Falk, Volkmar; Stamm, Christof
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    Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition
    (Theranostics, 2022) Huang, Grace; Cheng, Zhongjian; Hildebrand, Alycia; Wang, Chunlin; Cimini, Maria; Roy, Rajika; Lucchese, Anna Maria; Benedict, Cindy; Mallaredy, Vandana; Magadum, Ajit; Joladarashi, Darukeshwara; Thej, Charan; Gonzalez, Carolina; Trungcao, May; Garikipati, Venkata Naga Srikanth; Elrod, John W; Koch, Walter J; Kishore, Raj
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    Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure
    (Journal of Molecular and Cellular Cardiology, 2022-06) Garbincius, Joanne F; Luongo, Timothy S; Jadiya, Pooja; Hildebrand, Alycia N; Kolmetzky, Devin W; Mangold, Adam S; Roy, Rajika; Ibetti, Jessica; Nwokedi, Mary; Koch, Walter J; Elrod, John W
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    Epithelial-to-Mesenchymal Transition Enhances the Cardioprotective Capacity of Human Amniotic Epithelial Cells
    (Cell Transplantation, 2015-06) Roy, Rajika; Kukucka, Marian; Messroghli, Daniel; Kunkel, Désirée; Brodarac, Andreja; Klose, Kristin; Geißler, Sven; Becher, Peter Moritz; Kang, Sung Keun; Choi, Yeong-Hoon; Stamm, Christof
    The amniotic epithelium consists of cells exhibiting mature epitelial cell characteristics, but also varying degrees of stemness. We tested the hypothesis that induction of epithelial-to-mesenchymal transition (EMT) in amniotic epitelial cells (AECs) derived from human placenta enhances their capacity to support the ischemic myocardium. In response to incubation with transforming growth factor-β1 (TGF-β1) protein, AECs lost their cobblestone morphology and acquired a fibroblastoid shape, associated with downregulation of E-cadherin, upregulation of N-cadherin, Akt phosphorylation, and intracellular periostin translocation. EMT—AECs displayed greatly enhanced mobility and secreted gelatinase activity compared with naive AECs. The surface presentation of CD105 and CD73 decreased, and RNA microarray analysis mirrored the loss of epithelial characteristics and transcriptional profile. Unmodified AECs and EMT—AECs were then injected intramyocardially in fully immunocompetent mice after permanent LAD ligation, and heart function was followed by MRI as well as 2D speckle tracking echocardiography after 4 weeks. EMT—AEC-treated infarct hearts displayed better global systolic function and improved longitudinal strain rate in the area of interest. Although no signals of human cells were detectable by histology, infarct size was smaller in EMT—AEC-treated hearts, associated with fewer TUNEL-positive cells and upregulation of periostin, while blood vessel density was increased in both ACE- and EMT—AEC-treated hearts. We conclude that EMT enhances the cardioprotective effects of human AECs.
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    G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure
    (Cardiovascular Research, 2022-01-07) de Lucia, Claudio; Grisanti, Laurel A; Borghetti, Giulia; Piedepalumbo, Michela; Ibetti, Jessica; Lucchese, Anna Maria; Barr, Eric W; Roy, Rajika; Okyere, Ama Dedo; Murphy, Haley Christine; Gao, Erhe; Rengo, Giuseppe; Houser, Steven R; Tilley, Douglas G; Koch, Walter J
    Abstract Aims  Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included the examination of specific cardiac immune and inflammatory responses. Methods and results  Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T-lymphocytes at 4-days and 8-weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI. Conclusions  Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.
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    Genomic Binding Patterns of Forkhead Box Protein O1 Reveal Its Unique Role in Cardiac Hypertrophy
    (Circulation, 2020-09) Pfleger, Jessica; Coleman, Ryan C; Ibetti, Jessica; Roy, Rajika; Kyriazis, Ioannis D; Gao, Erhe; Drosatos, Konstantinos; Koch, Walter J
    Background: Cardiac hypertrophic growth is mediated by robust changes in gene expression and changes that underlie the increase in cardiomyocyte size. The former is regulated by RNA polymerase II (pol II) de novo recruitment or loss; the latter involves incremental increases in the transcriptional elongation activity of pol II that is preassembled at the transcription start site. The differential regulation of these distinct processes by transcription factors remains unknown. Forkhead box protein O1 (FoxO1) is an insulin-sensitive transcription factor that is also regulated by hypertrophic stimuli in the heart. However, the scope of its gene regulation remains unexplored. Methods: To address this, we performed FoxO1 chromatin immunoprecipitation–deep sequencing in mouse hearts after 7 days of isoproterenol injections (3 mg·kg −1 ·mg −1 ), transverse aortic constriction, or vehicle injection/sham surgery. Results: Our data demonstrate increases in FoxO1 chromatin binding during cardiac hypertrophic growth, which positively correlate with extent of hypertrophy. To assess the role of FoxO1 on pol II dynamics and gene expression, the FoxO1 chromatin immunoprecipitation–deep sequencing results were aligned with those of pol II chromatin immunoprecipitation–deep sequencing across the chromosomal coordinates of sham- or transverse aortic constriction–operated mouse hearts. This uncovered that FoxO1 binds to the promoters of 60% of cardiac-expressed genes at baseline and 91% after transverse aortic constriction. FoxO1 binding is increased in genes regulated by pol II de novo recruitment, loss, or pause-release. In vitro, endothelin-1– and, in vivo, pressure overload–induced cardiomyocyte hypertrophic growth is prevented with FoxO1 knockdown or deletion, which was accompanied by reductions in inducible genes, including Comtd1 in vitro and Fstl1 and Uck2 in vivo. Conclusions: Together, our data suggest that FoxO1 may mediate cardiac hypertrophic growth via regulation of pol II de novo recruitment and pause-release; the latter represents the majority (59%) of FoxO1-bound, pol II–regulated genes after pressure overload. These findings demonstrate the breadth of transcriptional regulation by FoxO1 during cardiac hypertrophy, information that is essential for its therapeutic targeting.
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    Glutaminolysis is Essential for Myofibroblast Persistence and In Vivo Targeting Reverses Fibrosis and Cardiac Dysfunction in Heart Failure
    (Circulation, 2022-05-24) Gibb, Andrew A; Murray, Emma K; Huynh, Anh T; Gaspar, Ryan B; Ploesch, Tori L; Bedi, Ken; Lombardi, Alyssa A; Lorkiewicz, Pawel K; Roy, Rajika; Arany, Zolt; Kelly, Daniel P; Margulies, Kenneth B; Hill, Bradford G; Elrod, John W
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    Impact of heart failure on the behavior of human neonatal stem cells in vitro
    (Journal of Translational Medicine, 2013-12) Klose, Kristin; Roy, Rajika; Brodarac, Andreja; Kurtz, Andreas; Ode, Andrea; Kang, Kyung-Sun; Bieback, Karen; Choi, Yeong-Hoon; Stamm, Christof
    Abstract Background Clinical cardiac cell therapy using autologous somatic stem cells is restricted by age and disease-associated impairment of stem cell function. Juvenile cells possibly represent a more potent alternative, but the impact of patient-related variables on such cell products is unknown. We therefore evaluated the behavior of neonatal cord blood mesenchymal stem cells (CB-MSC) in the presence of serum from patients with advanced heart failure (HF). Methods Human serum was obtained from patients with severe HF (n = 21) and from healthy volunteers (n = 12). To confirm the systemic quality of HF in the sera, TNF-α and IL-6 were quantified. CB-MSC from healthy neonates were cultivated for up to 14 days in medium supplemented with 10% protein-normalized human HF or control serum or fetal calf serum (FCS). Results All HF sera contained increased cytokine concentrations (IL-6, TNF-α). When exposed to HF serum, CB-MSC maintained basic MSC properties as confirmed by immunophenotyping and differentiation assays, but clonogenic cells were reduced in number and gave rise to substantially smaller colonies in the CFU-F assay. Cell cycle analysis pointed towards G1 arrest. CB-MSC metabolic activity and proliferation were significantly impaired for up to 3 days as measured by MTS turnover, BrdU incorporation and DAPI + nuclei counting. On day 5, however, CB-MSC growth kinetics approached control serum levels, though protein expression of cell cycle inhibitors (p21, p27), and apoptosis marker Caspase 3 remained elevated. Signal transduction included the stress and cytokine-induced JNK and ERK1/2 MAP kinase pathways. Conclusions Heart failure temporarily inhibits clonality and proliferation of “healthy” juvenile MSC in vitro. Further studies should address the in vivo and clinical relevance of this finding.
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    Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment
    (Circulation Research, 2020-01-31) Yue, Yujia; Wang, Chunlin; Benedict, Cindy; Huang, Grace; Truongcao, May; Roy, Rajika; Cimini, Maria; Garikipati, Venkata Naga Srikanth; Cheng, Zhongjian; Koch, Walter J; Kishore, Raj
    Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC–derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell–derived exosomes (TNFα inflamed mouse cardiac endothelial cell–derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB–dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome–mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.
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    Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.
    (American journal of physiology. Heart and circulatory physiology, 2020-05) Lieu, Melissa; Traynham, Christopher J; de Lucia, Claudio; Pfleger, Jessica; Piedepalumbo, Michela; Roy, Rajika; Petovic, Jennifer; Landesberg, Gavin; Forrester, Steven J; Hoffman, Matthew; Grisanti, Laurel A; Yuan, Ancai; Gao, Erhe; Drosatos, Konstantinos; Eguchi, Satoru; Scalia, Rosario; Tilley, Douglas G; Koch, Walter J
    Nitric oxide (NO) and S-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled receptor (GPCR) kinase 2 (GRK2) activity via S-nitrosylation of GRK2 at cysteine 340 (C340). This maintains GPCR homeostasis, including β-adrenergic receptors, through curbing receptor GRK2-mediated desensitization. Previously, we have developed a knockin mouse (GRK2-C340S) where endogenous GRK2 is resistant to dynamic S-nitrosylation, which led to increased GRK2 desensitizing activity. This unchecked regulation of cardiac GRK2 activity resulted in significantly more myocardial damage after ischemic injury that was resistant to NO-mediated cardioprotection. Although young adult GRK2-C340S mice show no overt phenotype, we now report that as these mice age, they develop significant cardiovascular dysfunction due to the loss of SNO-mediated GRK2 regulation. This pathological phenotype is apparent as early as 12 mo of age and includes reduced cardiac function, increased cardiac perivascular fibrosis, and maladaptive cardiac hypertrophy, which are common maladies found in patients with cardiovascular disease (CVD). There are also vascular reactivity and aortic abnormalities present in these mice. Therefore, our data demonstrate that a chronic and global increase in GRK2 activity is sufficient to cause cardiovascular remodeling and dysfunction, likely due to GRK2's desensitizing effects in several tissues. Because GRK2 levels have been reported to be elevated in elderly CVD patients, GRK2-C340 mice can give insight into the aged-molecular landscape leading to CVD.NEW & NOTEWORTHY Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.
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    MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis
    (Frontiers in Immunology) Zhong, Chao; Min, Kisuk; Zhao, Zhiqiang; Zhang, Cheng; Gao, Erhe; Huang, Yan; Zhang, Xinbo; Baldini, Margaret; Roy, Rajika; Yang, Xiaofeng; Koch, Walter J; Bennett, Anton M; Yu, Jun
    Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.
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    Not All β-Receptors Appear the Same in Heart Failure: Emergence of β3-Agonists as a Therapeutic Option
    (Circulation: Heart Failure, 2022-07) Roy, Rajika; Koch, Walter J