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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 RI\u03b1 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 RI\u03b1 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<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) alone is sufficient to induce RI\u03b1 protein downregulation. Transient increase of RI\u03b1 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 RI\u03b1 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 RI\u03b1 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.<\/jats:p><jats:p>NEW &amp; 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 RI\u03b1, 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.<\/jats:p>","DOI":"10.1152\/ajpheart.00237.2019","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T14:42:52Z","timestamp":1572619372000},"page":"H1231-H1242","source":"Crossref","is-referenced-by-count":39,"title":["Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RI\u03b1"],"prefix":"10.1152","volume":"317","author":[{"given":"Kristofer J.","family":"Haushalter","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California"},{"name":"Veterans Affairs San Diego Healthcare System, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M.","family":"Schilling","sequence":"additional","affiliation":[{"name":"Veterans Affairs San Diego Healthcare System, 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