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

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dc.contributor.author송영-
dc.date.accessioned2020-11-05T07:21:46Z-
dc.date.available2020-11-05T07:21:46Z-
dc.date.issued2019-12-
dc.identifier.issn0363-6135-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/179832-
dc.description.abstractType 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., H2O2) 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.NEW & NOTEWORTHY 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherAmerican Physiological Society-
dc.relation.isPartOfAMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHA Kinase Anchor Proteins / genetics-
dc.subject.MESHA Kinase Anchor Proteins / metabolism-
dc.subject.MESHAnimals-
dc.subject.MESHCell Line-
dc.subject.MESHCells, Cultured-
dc.subject.MESHCyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics-
dc.subject.MESHCyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism*-
dc.subject.MESHMale-
dc.subject.MESHMice-
dc.subject.MESHMice, Inbred C57BL-
dc.subject.MESHMitochondria, Heart / metabolism-
dc.subject.MESHMitochondria, Heart / ultrastructure-
dc.subject.MESHMyocardial Reperfusion Injury / metabolism*-
dc.subject.MESHMyocardial Reperfusion Injury / pathology-
dc.subject.MESHMyocytes, Cardiac / metabolism-
dc.subject.MESHReactive Oxygen Species / metabolism*-
dc.subject.MESHSignal Transduction-
dc.titleCardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Anesthesiology and Pain Medicine (마취통증의학교실)-
dc.contributor.googleauthorKristofer J Haushalter-
dc.contributor.googleauthorJan M Schilling-
dc.contributor.googleauthorYoung Song-
dc.contributor.googleauthorMira Sastri-
dc.contributor.googleauthorGuy A Perkins-
dc.contributor.googleauthorStefan Strack-
dc.contributor.googleauthorSusan S Taylor-
dc.contributor.googleauthorHemal H Patel-
dc.identifier.doi10.1152/ajpheart.00237.2019-
dc.contributor.localIdA02036-
dc.relation.journalcodeJ00105-
dc.identifier.eissn1522-1539-
dc.identifier.pmid31674811-
dc.identifier.urlhttps://journals.physiology.org/doi/full/10.1152/ajpheart.00237.2019-
dc.subject.keywordA-kinase anchoring protein 1-
dc.subject.keywordPKA regulatory subunit Riα-
dc.subject.keywordischemia-reperfusion injury-
dc.subject.keywordmitochondria-
dc.subject.keywordoxidative stress-
dc.contributor.alternativeNameSong, Young-
dc.contributor.affiliatedAuthor송영-
dc.citation.volume317-
dc.citation.number6-
dc.citation.startPageH1231-
dc.citation.endPageH1242-
dc.identifier.bibliographicCitationAMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol.317(6) : H1231-H1242, 2019-12-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers

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