Microtubule stabilization in pressure overload cardiac hypertrophy.
Increased microtubule density, for which microtubule stabilization is one potential mechanism, causes contractile dysfunction in cardiac hypertrophy. After microtubule assembly, alpha-tubulin undergoes two, likely sequential, time-dependent posttranslational changes: reversible carboxy-terminal detyrosination (Tyr-tubulin left and right arrow Glu-tubulin) and then irreversible deglutamination (Glu-tubulin --> Delta2-tubulin), such that Glu- and Delta2-tubulin are markers for long-lived, stable microtubules. Therefore, we generated antibodies for Tyr-, Glu-, and Delta2-tubulin and used them for staining of right and left ventricular cardiocytes from control cats and cats with right ventricular hypertrophy. Tyr- tubulin microtubule staining was equal in right and left ventricular cardiocytes of control cats, but Glu-tubulin and Delta2-tubulin staining were insignificant, i.e., the microtubules were labile. However, Glu- and Delta2-tubulin were conspicuous in microtubules of right ventricular cardiocytes from pressure overloaded cats, i.e., the microtubules were stable. This finding was confirmed in terms of increased microtubule drug and cold stability in the hypertrophied cells. In further studies, we found an increase in a microtubule binding protein, microtubule-associated protein 4, on both mRNA and protein levels in pressure-hypertrophied myocardium. Thus, microtubule stabilization, likely facilitated by binding of a microtubule-associated protein, may be a mechanism for the increased microtubule density characteristic of pressure overload cardiac hypertrophy.
Sato
H
H
Cardiology Section of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29401, USA.
Nagai
T
T
Kuppuswamy
D
D
Narishige
T
T
Koide
M
M
Menick
D R
DR
Cooper
G
G
D000818:Animals; D001794:Blood Pressure; D001810:Blood Volume; D006332:Cardiomegaly / Q000473:pathology*; D002415:Cats; D015977:Eukaryotic Initiation Factor-1; D019084:Fluorescent Antibody Technique, Indirect; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000648:ultrastructure*; D010448:Peptide Initiation Factors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D014404:Tubulin / Q000378:metabolism*
D015977:Eukaryotic Initiation Factor-1; D008869:Microtubule-Associated Proteins; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D014404:Tubulin; C026022:eukaryotic peptide initiation factor-1A