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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
- Source :
- Cardiovascular Research
- Publication Year :
- 2020
-
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.<br />Graphical Abstract
- Subjects :
- 0301 basic medicine
G-Protein-Coupled Receptor Kinase 5
Leukocyte migration
Heart disease
Physiology
medicine.medical_treatment
Myocardial Infarction
030204 cardiovascular system & hematology
Ventricular Function, Left
0302 clinical medicine
Leukocytes
AcademicSubjects/MED00200
Myocytes, Cardiac
Myocardial infarction
Inflammation Mediator
Mice, Knockout
Left ventricle
Chemotaxis, Leukocyte
Cytokine
Knockout mouse
Cytokines
medicine.symptom
Inflammation Mediators
Cardiology and Cardiovascular Medicine
Cardiac Remodelling and Heart Failure
Signal Transduction
Cardiac function curve
medicine.medical_specialty
Myocardial ischemia
Heart Diseases
Inflammation
Cardiomegaly
03 medical and health sciences
Physiology (medical)
Internal medicine
medicine
Ventricular Pressure
Humans
Animals
Ischemic heart failure
Cardiac remodeling
Heart Failure
Animal
business.industry
Stroke Volume
Original Articles
Leukocyte
medicine.disease
Myocardial Contraction
Disease Models, Animal
030104 developmental biology
Endocrinology
Immune system
Heart failure
business
Transcriptome
Subjects
Details
- ISSN :
- 17553245
- Volume :
- 118
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cardiovascular research
- Accession number :
- edsair.doi.dedup.....ada6f4231a811bb1967fe2068b339fa9