Abstract 396: GRK5-mediated Exacerbation of Ischemic Heart Failure Involves Cardiac Immune-Inflammatory Responses
| Autor: | Claudio de Lucia, Laurel A Grisanti, Jessica Ibetti, Anna M Lucchese, Erhe Gao, Douglas G Tilley, Dario Leosco, Nicola Ferrara, Giuseppe Rengo, Walter J Koch |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Circulation Research. 121 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.121.suppl_1.396 |
| Popis: | Rationale: Coronary artery disease and subsequent myocardial ischemia (MI) are the most common cause of heart failure (HF) in the US. G protein-coupled receptor (GPCR) kinase 5 (GRK5) has been shown to be upregulated in failing human myocardium. While the canonical role of GRKs is to desensitize receptors via phosphorylation, it has been shown that GRK5 can also locate to the nucleus of cardiomyocytes where it can exert GPCR-independent effects that promote maladaptive cardiac hypertrophy after hypertrophic stress. Despite numerous data indicating the importance of GRK5 in hypertrophy, it is still unknown if GRK5 has a role in ischemic heart disease. Objective: In this study, we investigated the critical role that GRK5 plays after myocardial ischemic injury with a novel aspect being the regulation of immune and inflammatory responses including recruitment of immune cells to the injured heart. Methods and Results: Cardiac-specific GRK5 transgenic mice (Tg-GRK5) and non-transgenic littermate (NLC) control mice were subjected to MI. Tg-GRK5-HF mice showed decreased cardiac function (both global and segmental contractility) as well as augmented left ventricular diameters and volumes compared to NLC-HF mice. Heart weight (HW) to body weight or tibia length ratios as well as mRNA expression of all major adverse remodeling-associated biomarkers (ANF, BNP, b-MHC) were increased in the TgGRK5-HF compared to NLC-HF. Cardiac fibrosis in the border zone (BZ) area as well as mRNA levels of Collagen-1 (Col-1), Col-3, MMP2 and CTGF were higher in TgGRK5-HF compared to NLC-HF, strongly suggesting increased adverse remodeling. Inflammatory Cytokines (IL-6 and IL-1beta) were augmented in TgGRK5-HF compared to NLC-HF and contribute at least in part to increased immune cell recruitment in the heart. In fact, we found both Neutrophils and T-lymphocytes (T- cells) augmented in the BZ and infarct zone. Conclusions: Our study shows that cardiac GRK5 has a detrimental effect during ischemic HF. GRK5 overexpression causes reduced cardiac function and increased immune cell recruitment/inflammation. Further, these results suggest GRK5 as a potential therapeutic target to limit HF development after ischemic injury. |
| Databáze: | OpenAIRE |
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