Claudio de Lucia, MD, Ph.D. Center for Translational Medicine, Lewis Katz School of Medicine, Temple University speaks about G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.Link to Article:https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvab044/6131786Synopsis:Objectives -The most common cause of heart failure (HF) is myocardial infarction (MI). In animal models, the G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy. The function of GRK5 in ischemic heart disease, on the other hand, is still unknown. In this research, we looked at whether myocardial GRK5 is essential after a heart attack in mice, as well as specific cardiac immune and inflammatory responses.Methods and outcomes -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) mice, were all given a MI and their functional and structural changes, as well as their outcomes, were investigated. When compared to NLC post-MI mice, TgGRK5 post-MI mice had a lower cardiac function, a larger left ventricular dimension, and a lower survival rate. TgGRK5 mice had more cardiac hypertrophy and fibrosis, as well as fetal gene expression, after MI than NLC mice. GRK5 elevation developed immuno-regulators in TgGRK5 mice, which led to increased and long-lasting leukocyte recruitment into the injured heart, and eventually to chronic cardiac inflammation. At 4-days and 8-weeks post-MI, we observed a rise in pro-inflammatory neutrophils and macrophages, as well as neutrophils, macrophages, and T-lymphocytes in TgGRK5 hearts. In contrast to WT post-MI mice, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (primarily monocytes) to the heart, increased contractility, and lower mortality. Surprisingly, cardiomyocyte-specific GRK2 transgenic mice did not exhibit the same phenotype as TgGRK5 mice and did not exhibit increased cardiac leukocyte migration or cytokine or chemokine output after MI.Final thoughts -In a murine model of post-ischemic HF, our findings show that myocyte GRK5 plays a critical and GRK-selective role in the control of leucocyte infiltration into the heart, cardiac function, and survival, indicating that GRK5 inhibition may be a therapeutic target for HF. - Heart Failure and Cardiomyopathies - 377_600c9efaa3c99

Claudio de Lucia, MD @cladelucia @templemedschool #HeartFailure #Cardiology #Heart #Research GRK5 contributes to impaired cardiac function and immune cell recruitment in post-ischemic hea...

Claudio de Lucia, MD @cladelucia @templemedschool #HeartFailure #Cardiology #Heart #Research GRK5 contributes to impaired cardiac function and immune cell recruitment in post-ischemic hea...

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Claudio de Lucia, MD, Ph.D. Center for Translational Medicine, Lewis Katz School of Medicine, Temple University speaks about G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.

Link to Article:
https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvab044/6131786

Synopsis:

Objectives -

The most common cause of heart failure (HF) is myocardial infarction (MI). In animal models, the G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy. The function of GRK5 in ischemic heart disease, on the other hand, is still unknown. In this research, we looked at whether myocardial GRK5 is essential after a heart attack in mice, as well as specific cardiac immune and inflammatory responses.

Methods and outcomes -

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) mice, were all given a MI and their functional and structural changes, as well as their outcomes, were investigated. When compared to NLC post-MI mice, TgGRK5 post-MI mice had a lower cardiac function, a larger left ventricular dimension, and a lower survival rate. TgGRK5 mice had more cardiac hypertrophy and fibrosis, as well as fetal gene expression, after MI than NLC mice. GRK5 elevation developed immuno-regulators in TgGRK5 mice, which led to increased and long-lasting leukocyte recruitment into the injured heart, and eventually to chronic cardiac inflammation. At 4-days and 8-weeks post-MI, we observed a rise in pro-inflammatory neutrophils and macrophages, as well as neutrophils, macrophages, and T-lymphocytes in TgGRK5 hearts. In contrast to WT post-MI mice, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (primarily monocytes) to the heart, increased contractility, and lower mortality. Surprisingly, cardiomyocyte-specific GRK2 transgenic mice did not exhibit the same phenotype as TgGRK5 mice and did not exhibit increased cardiac leukocyte migration or cytokine or chemokine output after MI.

Final thoughts -

In a murine model of post-ischemic HF, our findings show that myocyte GRK5 plays a critical and GRK-selective role in the control of leucocyte infiltration into the heart, cardiac function, and survival, indicating that GRK5 inhibition may be a therapeutic target for HF.

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