Cardiac ischemia/reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα.
Summary of "Cardiac ischemia/reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIα."
Type I PKA regulatory subunit alpha (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 global I/R injury in mouse hearts selectively down-regulated 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. HO) alone is sufficient to induce RIα protein down-regulation. 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 AKAP1-KO mice, where loss of AKAP1 expression leads to aberrant mitochondrial morphology manifested in SSM but not interfibrillar mitochondria (IFM). 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.
Affiliation
Journal Details
This article was published in the following journal.
Name: American journal of physiology. Heart and circulatory physiology
ISSN: 1522-1539
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/31674811
- DOI: http://dx.doi.org/10.1152/ajpheart.00237.2019
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Medical and Biotech [MESH] Definitions
Reperfusion Injury
Adverse functional, metabolic, or structural changes in ischemic tissues resulting from the restoration of blood flow to the tissue (REPERFUSION), including swelling; HEMORRHAGE; NECROSIS; and damage from FREE RADICALS. The most common instance is MYOCARDIAL REPERFUSION INJURY.
Myocardial Reperfusion
Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing MYOCARDIAL REPERFUSION INJURY.
Reperfusion
Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing REPERFUSION INJURY.
Ischemic Preconditioning, Myocardial
Exposure of myocardial tissue to brief, repeated periods of vascular occlusion in order to render the myocardium resistant to the deleterious effects of ISCHEMIA or REPERFUSION. The period of pre-exposure and the number of times the tissue is exposed to ischemia and reperfusion vary, the average being 3 to 5 minutes.
Myocardial Reperfusion Injury
Damage to the MYOCARDIUM resulting from MYOCARDIAL REPERFUSION (restoration of blood flow to ischemic areas of the HEART.) Reperfusion takes place when there is spontaneous thrombolysis, THROMBOLYTIC THERAPY, collateral flow from other coronary vascular beds, or reversal of vasospasm.
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