0 28

Cited 0 times in

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

Authors
 Kristofer J Haushalter  ;  Jan M Schilling  ;  Young Song  ;  Mira Sastri  ;  Guy A Perkins  ;  Stefan Strack  ;  Susan S Taylor  ;  Hemal H Patel 
Citation
 AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol.317(6) : H1231-H1242, 2019-12 
Journal Title
 AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 
ISSN
 0363-6135 
Issue Date
2019-12
MeSH
A Kinase Anchor Proteins / genetics ; A Kinase Anchor Proteins / metabolism ; Animals ; Cell Line ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics ; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria, Heart / metabolism ; Mitochondria, Heart / ultrastructure ; Myocardial Reperfusion Injury / metabolism* ; Myocardial Reperfusion Injury / pathology ; Myocytes, Cardiac / metabolism ; Reactive Oxygen Species / metabolism* ; Signal Transduction
Keywords
A-kinase anchoring protein 1 ; PKA regulatory subunit Riα ; ischemia-reperfusion injury ; mitochondria ; oxidative stress
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., 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.
Full Text
https://journals.physiology.org/doi/full/10.1152/ajpheart.00237.2019
DOI
10.1152/ajpheart.00237.2019
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Song, Young(송영) ORCID logo https://orcid.org/0000-0003-4597-387X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179832
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links