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Protein Tyrosine Nitration and Glutathionylation Impairs Pro‐Survival Mechanisms of Akt in CryABmut Cardiomyopathy in Mice
Author(s) -
Soorappan Rajasekaran Namakkal,
Varadharaj Saradhadevi,
Zhang Huali,
Zweier Jay L,
Benjamin Ivor J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.110.4
Subject(s) - protein kinase b , oxidative stress , cardiomyopathy , cancer research , tyrosine kinase , phosphorylation , heart failure , medicine , microbiology and biotechnology , chemistry , endocrinology , signal transduction , biology
Background Serine‐threonine Akt affords powerful cellular protection but the role of this pro‐survival pathway in hR120GCryAB‐TG cardiomyopathy remains poorly defined. We hypothesized that chronic oxidative modifications and sequestration of Akt could impair the pro‐survival mechanisms in the hR120GCryAB‐TG leading to heart failure. Methods To gain further insights, we have determined biochemical markers of oxidative modifications. Results Western blot and immunohistochemical analyses indicated increased protein kinase‐B (PKB/Akt) is sequestered into the protein aggregates containing hR120GCryAB in myopathic hearts compared with the non‐transgenic (NTG) controls. Increased S‐glutathionylation and tyrosine nitrosylation were present in the 3 and 6 months old TG mice, suggesting potential role in inactivation of pro‐survival mechanisms of Akt. Surprisingly, we found increased Akt kinase (substrate: GSK3‐α/β) activity in vitro in the hR120GCryAB‐TG hearts compared with the NTG, suggesting chronic Akt activation is coupled with cardiac hypertrophy and progression of cardiaomyopathy. Conclusions Taken together, these findings implicate chronic activation and sequestration of Akt in the pathogenesis of hR120GCryAB‐induced cardiotoxicity.