Browsing by Author "Ibetti, Jessica"
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Item Open Access 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 JGRK5 does not mediate pathological signaling in the heart if its nuclear translocation is disrupted.Item Open Access 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 JβARKct, 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.Item Open Access 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 WItem Open Access 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 JAbstract 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.Item Open Access 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 JBackground: 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.Item Open Access Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation(Science Signaling, 2018-12-11) Sato, Priscila Y; Chuprun, J Kurt; Grisanti, Laurel A; Woodall, Meryl C; Brown, Brett R; Roy, Rajika; Traynham, Christopher J; Ibetti, Jessica; Lucchese, Anna M; Yuan, Ancai; Drosatos, Konstantinos; Tilley, Doug G; Gao, Erhe; Koch, Walter JPreventing GRK2 from localizing to mitochondria lessens the damage induced by myocardial infarction.