Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα

Kristofer J Haushalter; Jan M Schilling; Young Song; Mira Sastri; Guy A Perkins; Stefan Strack; Susan S Taylor; Hemal H Patel

doi:10.1152/ajpheart.00237.2019

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Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα

Journal article

Open access

Peer reviewed

Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα

Kristofer J Haushalter, Jan M Schilling, Young Song, Mira Sastri, Guy A Perkins, Stefan Strack, Susan S Taylor and Hemal H Patel

American journal of physiology. Heart and circulatory physiology, Vol.317(6), pp.H1231-H1242

12/01/2019

DOI: 10.1152/ajpheart.00237.2019

PMCID: PMC6962616

PMID: 31674811

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Abstract

Type I PKA regulatory α-subunit (RIα; encoded by the Prkar1a gene) serves as the predominant inhibitor protein of the catalytic subunit of cAMP-dependent protein kinase (PKAc). However, recent evidence suggests that PKA signaling can be initiated by cAMP-independent events, especially within the context of cellular oxidative stress such as ischemia-reperfusion (I/R) injury. We determined whether RIα is actively involved in the regulation of PKA activity via reactive oxygen species (ROS)-dependent mechanisms during I/R stress in the heart. Induction of ex vivo global I/R injury in mouse hearts selectively downregulated RIα protein expression, whereas RII subunit expression appears to remain unaltered. Cardiac myocyte cell culture models were used to determine that oxidant stimulus (i.e., H O ) alone is sufficient to induce RIα protein downregulation. Transient increase of RIα expression (via adenoviral overexpression) negatively affects cell survival and function upon oxidative stress as measured by increased induction of apoptosis and decreased mitochondrial respiration. Furthermore, analysis of mitochondrial subcellular fractions in heart tissue showed that PKA-associated proteins are enriched in subsarcolemmal mitochondria (SSM) fractions and that loss of RIα is most pronounced at SSM upon I/R injury. These data were supported via electron microscopy in A-kinase anchoring protein 1 (AKAP1)-knockout mice, where loss of AKAP1 expression leads to aberrant mitochondrial morphology manifested in SSM but not interfibrillar mitochondria. Thus, we conclude that modification of RIα via ROS-dependent mechanisms induced by I/R injury has the potential to sensitize PKA signaling in the cell without the direct use of the canonical cAMP-dependent activation pathway. We uncovered a previously undescribed phenomenon involving oxidation-induced activation of PKA signaling in the progression of cardiac ischemia-reperfusion injury. Type I PKA regulatory subunit RIα, but not type II PKA regulatory subunits, is dynamically regulated by oxidative stress to trigger the activation of the catalytic subunit of PKA in cardiac myocytes. This effect may play a critical role in the regulation of subsarcolemmal mitochondria function upon the induction of ischemic injury in the heart.

Mitochondria, Heart - ultrastructure

Cell Line

Mitochondria, Heart - metabolism

Reactive Oxygen Species - metabolism

Signal Transduction

Mice, Inbred C57BL

Cells, Cultured

Male

A Kinase Anchor Proteins - genetics

Myocardial Reperfusion Injury - metabolism

Myocardial Reperfusion Injury - pathology

Animals

Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - genetics

Myocytes, Cardiac - metabolism

Mice

Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - metabolism

A Kinase Anchor Proteins - metabolism

Details

Title: Subtitle: Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα
Creators: Kristofer J Haushalter - Veterans Affairs San Diego Healthcare System, San Diego, California
Jan M Schilling - Department of Anesthesiology, University of California, San Diego, La Jolla, California
Young Song - Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, South Korea
Mira Sastri - Department of Pharmacology, University of California, San Diego, La Jolla, California
Guy A Perkins - National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California
Stefan Strack - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa
Susan S Taylor - Department of Pharmacology, University of California, San Diego, La Jolla, California
Hemal H Patel - Department of Anesthesiology, University of California, San Diego, La Jolla, California
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.317(6), pp.H1231-H1242
DOI: 10.1152/ajpheart.00237.2019
PMID: 31674811
PMCID: PMC6962616
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: United States
Grant note: I01 BX001963 / BLRD VA
Language: English
Date published: 12/01/2019
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984068227402771

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