Browsing by Author "Lucchese, Anna Maria"

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Open Access
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, Rakija; 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
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 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.
Open Access
Podoplanin neutralization improves cardiac remodeling and function after acute myocardial infarction.
(JCI insight, 2019-07) Cimini, Maria; Garikipati, Venkata Naga Srikanth; de Lucia, Claudio; Cheng, Zhongjian; Wang, Chunlin; Truongcao, May M; Lucchese, Anna Maria; Roy, Rajika; Benedict, Cindy; Goukassian, David A; Koch, Walter J; Kishore, Raj
Podoplanin, a small mucine-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. Podoplanin binds to CLEC-2, a C-type lectin-like receptor 2 highly expressed by CD11bhigh cells following inflammatory stimuli. Why podoplanin expression appears only after organ injury is currently unknown. Here, we characterize the role of podoplanin in different stages of myocardial repair after infarction and propose a podoplanin-mediated mechanism in the resolution of post-MI inflammatory response and cardiac repair. Neutralization of podoplanin led to significant improvements in the left ventricular functions and scar composition in animals treated with podoplanin neutralizing antibody. The inhibition of the interaction between podoplanin and CLEC-2 expressing immune cells in the heart enhances the cardiac performance, regeneration and angiogenesis post MI. Our data indicates that modulating the interaction between podoplanin positive cells with the immune cells after myocardial infarction positively affects immune cell recruitment and may represent a novel therapeutic target to augment post-MI cardiac repair, regeneration and function.