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PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Nagoshi, Tomohisa Matsui, Takashi Aoyama, Takuma Leri, Annarosa Anversa, Piero Li, Ling Ogawa, Wataru Monte, Federica Del Grazette, Luanda P. Rosenzweig, Anthony |
| Copyright Year | 2005 |
| Abstract | Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt-Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt-Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate-1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt-Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/23000/23073/JCI0523073.pdf |
| PubMed reference number | 16007268v1 |
| Volume Number | 115 |
| Issue Number | 8 |
| Journal | The Journal of clinical investigation |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase Cumulative Trauma Disorders Gene Transfer Heart failure IRS2 protein, human Infarction Ischemia Large Patients Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Reperfusion Injury Reperfusion Therapy Threonine insulin receptor substrate 1 protein |
| Content Type | Text |
| Resource Type | Article |
