GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion

Franco, Antonietta; Sorriento, Daniela; Gambardella, Jessica; Pacelli, Roberto; Prevete, Nella; Procaccini, Claudio; Matarese, Giuseppe; Trimarco, Bruno; Iaccarino, Guido; Ciccarelli, Michele

doi:10.1038/s41420-018-0028-7

Cited by 34 publications

(30 citation statements)

References 28 publications

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“…Studies have shown data that GRK may act both a protector against and a promotor for death following ischemic injury (45,53). Removal of cardiac-specific GRK2 has been linked to embryonic cardiovascular development, adult cardiac dilatation, early atherosclerosis and inhibited angiogenesis in mice (42,(54)(55)(56)(57). Franco et al evaluated cell cultures with knockdown or overexpressed GRK2 3-8 h after exposure of a single dose of 4 Gy.…”

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

“…Franco et al evaluated cell cultures with knockdown or overexpressed GRK2 3-8 h after exposure of a single dose of 4 Gy. Knockdown of GRK caused morphologic mitochondrial changes, reduced membrane potential and reduced mitochondrial function (42). The overexpression of GRK2 protected mitochondria from radiation damage (42).…”

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

“…Knockdown of GRK caused morphologic mitochondrial changes, reduced membrane potential and reduced mitochondrial function (42). The overexpression of GRK2 protected mitochondria from radiation damage (42). Furthermore, it was demonstrated that in the presence of heat shock proteins, GRK2 interacts with mitofusins (MFN-1 and MFN-2), key regulators of mitochondrial fission and fusion (42,58).…”

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

“…The overexpression of GRK2 protected mitochondria from radiation damage (42). Furthermore, it was demonstrated that in the presence of heat shock proteins, GRK2 interacts with mitofusins (MFN-1 and MFN-2), key regulators of mitochondrial fission and fusion (42,58). Additional studies are required to understand the chronic response of GRK to radiation, but GRK-related pathways may be important targets to drive mitochondrial protection from radiation-induced damage.…”

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

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The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside

Livingston

Schlaak

Puckett

et al. 2020

Front. Cardiovasc. Med.

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Radiation is a key modality in the treatment of many cancers; however, it can also affect normal tissues adjacent to the tumor, leading to toxic effects. Radiation to the thoracic region, such as that received as part of treatment for breast and lung cancer, can result in incidental dose to the heart, leading to cardiac dysfunction, such as pericarditis, coronary artery disease, ischemic heart disease, conduction defects, and valvular dysfunction. The underlying mechanisms for these morbidities are currently being studied but are not entirely understood. There has been increasing focus on the role of radiation-induced mitochondrial dysfunction and the ensuing impact on various cardiac functions in both preclinical models and in humans. Cardiomyocyte mitochondria are critical to cardiac function, and mitochondria make up a substantial part of a cardiomyocyte's volume. Mitochondrial dysfunction can also alter other cell types in the heart. This review summarizes several factors related to radiation-induced mitochondrial dysfunction in cardiomyocytes and endothelial cells. These factors include mitochondrial DNA mutations, oxidative stress, alterations in various mitochondrial function-related transcription factors, and apoptosis. Through improved understanding of mitochondria-dependent mechanisms of radiation-induced heart dysfunction, potential therapeutic targets can be developed to assist in prevention and treatment of radiation-induced heart damage.

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Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

Section: Mitochondria and Oxidative Stressmentioning

confidence: 99%

See 2 more Smart Citations

The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside

Livingston

Schlaak

Puckett

et al. 2020

Front. Cardiovasc. Med.

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“…7 In particular, alterations of cardiac metabolism are an early marker of HF that anticipates the systolic dysfunction and ventricle remodelling. 7 Furthermore, GRK2 localizes at mitochondria 8 where it seems, in the long run, to promote a pro-death signal pathway. 9 Although previous literature shows the possibility to restore cardiac contractility by targeting GRK2 with different strategies, so far, no information is available as to the effects of GRK2 inhibition on cardiac metabolism and mitochondrial function in the failing heart.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure

et al. 2020

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Aims The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF. Methods and results C7 was initially tested on adult mice ventricular myocyte from wild type and GRK2 myocardial deficient mice (GRK2-cKO), to assess the selectivity on GRK2 inhibition. Then, chronic infusion of 2 mg/kg/day of C7 was performed in HF mice with cryogenic myocardial infarction. Cardiac function in vivo was assessed by echocardiography and cardiac catheterization. Histological, biochemical, and metabolic studies were performed on heart samples at time points. C7 induces a significant increase of contractility in wild type but not in adult ventricle myocytes from GRK2-cKO mice, thus confirming C7 selectivity for GRK2. In HF mice, 4 weeks of treatment with C7 improved metabolic features, including mitochondrial organization and function, and restored the biochemical and contractile responses. Conclusions GRK2 is a critical molecule in the physiological regulation of cardiac metabolism. Its alterations in the failing heart can be pharmacologically targeted, leading to the correction of metabolic and functional abnormalities observed in HF.

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Pathophysiology of Takotsubo syndrome – a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology – Part 1: overview and the central role for catecholamines and sympathetic nervous system

Ömerovic

Citro

Bossone

et al. 2022

European J of Heart Fail

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This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β‐adrenergic receptor signalling, G‐protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model.

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GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion

Cited by 34 publications

References 28 publications

The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside

The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside

Pharmacological inhibition of GRK2 improves cardiac metabolism and function in experimental heart failure

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