Protein Kinase A Catalytic Subunit Alters Cardiac Mitochondrial Redox State and Membrane Potential Via the Formation of Reactive Oxygen Species

Nagasaka, Shiro; Katoh, Hideki; Niu, Chun Feng; Matsui, Saori; Urushida, Tsuyoshi; Satoh, Hiroshi; Watanabe, Yasuhide; Hayashi, Hideharu

doi:10.1253/circj.71.429

Cited by 26 publications

(20 citation statements)

References 46 publications

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“…6D). PKA signaling has been shown to affect mitochondrial redox state through ROS production (33). Because PKAc and AKIP1 interact, this protein complex may also influence PKAc substrates, possibly in the mitochondria.…”

Section: Akip1 Overexpression Increases Mitochondrial-localized Akip1mentioning

confidence: 99%

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

Sastri¹,

Haushalter²,

Panneerselvam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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cAMP-dependent protein kinase (PKA) regulates a myriad of functions in the heart, including cardiac contractility, myocardial metabolism, and gene expression. However, a molecular integrator of the PKA response in the heart is unknown. Here, we show that the PKA adaptor A-kinase interacting protein 1 (AKIP1) is up-regulated in cardiac myocytes in response to oxidant stress. Mice with cardiac gene transfer of AKIP1 have enhanced protection to ischemic stress. We hypothesized that this adaptation to stress was mitochondrialdependent. AKIP1 interacted with the mitochondrial localized apoptosis inducing factor (AIF) under both normal and oxidant stress. When cardiac myocytes or whole hearts are exposed to oxidant and ischemic stress, levels of both AKIP1 and AIF were enhanced. AKIP1 is preferentially localized to interfibrillary mitochondria and up-regulated in this cardiac mitochondrial subpopulation on ischemic injury. Mitochondria isolated from AKIP1 genetransferred hearts showed increased mitochondrial localization of AKIP1, decreased reactive oxygen species generation, enhanced calcium tolerance, decreased mitochondrial cytochrome C release, and enhance phosphorylation of mitochondrial PKA substrates on ischemic stress. These observations highlight AKIP1 as a critical molecular regulator and a therapeutic control point for stress adaptation in the heart. ischemia/reperfusion | oxidative stress

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Section: Akip1 Overexpression Increases Mitochondrial-localized Akip1mentioning

confidence: 99%

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

Sastri¹,

Haushalter²,

Panneerselvam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…12 The PKA catalytic subunit alters the cardiac mitochondrial redox state and the MMP via mitochondrial ROS generation. 13 Uncoupling protein 2 (UCP2), an anion transporter embedded in the inner mitochondrial membrane, acts as an adaptive antioxidant defense factor to protect against endothelial dysfunction in cardiovascular diseases.…”

mentioning

confidence: 99%

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

Xiong

Wang

et al. 2016

Hypertension

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“…Previous studies have shown a role of mitochondrial ROS production in the β-adrenergic signaling in cardiomyocytes. For instance, application of the PKA catalytic subunit resulted in increased ROS production and altered the redox state in mitochondria of permeabilized rat cardiomyocytes [57]. Moreover, acute β-adrenergic stimulation with ISO resulted in a cAMP-PKA-dependent increase in mitochondrial ROS production in intact ventricular cardiomyocytes of WT mice [11].…”

Section: Discussionmentioning

confidence: 99%

The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome

et al. 2016

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The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice). We hypothesized that cardiomyocytes of mice with the metabolic syndrome would experience excessive ROS levels that trigger cellular dysfunctions. Fluorescent dyes and confocal microscopy were used to assess mitochondrial ROS production, cellular Ca2+ handling and contractile function in freshly isolated adult cardiomyocytes. Immunofluorescence, western blot and enzyme assay were used to study protein biochemistry. Unexpectedly, our results point towards decreased cardiac ROS signaling in a stable, chronic phase of the metabolic syndrome because: β-adrenergic-induced increases in the amplitude of intracellular Ca2+ signals were insensitive to antioxidant treatment; mitochondrial ROS production showed decreased basal rate and smaller response to β-adrenergic stimulation. Moreover, control hearts and hearts with the metabolic syndrome showed similar basal levels of ROS-mediated protein modification, but only control hearts showed increases after β-adrenergic stimulation. In conclusion, in contrast to the situation in control hearts, the cardiomyocyte response to acute β-adrenergic stimulation does not involve increased mitochondrial ROS production in a stable, chronic phase of the metabolic syndrome. This can be seen as a beneficial adaptation to prevent excessive ROS levels.

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Protein Kinase A Catalytic Subunit Alters Cardiac Mitochondrial Redox State and Membrane Potential Via the Formation of Reactive Oxygen Species

Cited by 26 publications

References 46 publications

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

A kinase interacting protein (AKIP1) is a key regulator of cardiac stress

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome

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