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(Circulation Research. 2006;99:626.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Inhibition of Nuclear Import of Calcineurin Prevents Myocardial Hypertrophy

Matthias Hallhuber, Natalie Burkard, Rongxue Wu, Mamta H. Buch, Stefan Engelhardt, Lutz Hein, Ludwig Neyses, Kai Schuh, Oliver Ritter

From the Department of Medicine I (M.H., N.B., R.W., O.R.); Institute of Physiology (K.S.); and Rudolf-Virchow-Center (S.E.), DFG-Research Center for Experimental Biomedicine, University of Wuerzburg, Germany; University Department of Medicine (M.H.B., L.N.), Manchester Royal Infirmary, UK; and the Institute of Experimental and Clinical Pharmacology and Toxicology (L.H.), University of Freiburg, Germany.

Correspondence to Oliver Ritter, MD, Department of Medicine I, University of Wuerzburg, Josef Schneider Str. 2, 97080 Wuerzburg, Germany. E-mail Ritter_O{at}klinik.uni-wuerzburg.de

The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus with the transcription factor nuclear factor of activated T cells (NF-AT). This study identifies a nuclear localization sequence (NLS) and a nuclear export signal (NES) in the sequence of calcineurin. Furthermore we identified the nuclear cargo protein importinß₁ to be responsible for nuclear translocation of calcineurin. Inhibition of the calcineurin/importin interaction by a competitive peptide (KQECKIKYSERV), which mimicked the calcineurin NLS, prevented nuclear entry of calcineurin. A noninhibitory control peptide did not interfere with the calcineurin/importin binding. Using this approach, we were able to prevent the development of myocardial hypertrophy. In angiotensin II-stimulated cardiomyocytes, [³H]-leucine incorporation (159%±9 versus 111%±11; P<0.01) and cell size were suppressed significantly by the NLS peptide compared with a control peptide. The NLS peptide inhibited calcineurin/NF-AT transcriptional activity (227%±11 versus 133%±8; P<0.01), whereas calcineurin phosphatase activity was unaffected (298%±9 versus 270%±11; P=NS). We conclude that calcineurin is not only capable of dephosphorylating NF-AT, thus enabling its nuclear import, but the presence of calcineurin in the nucleus is also important for full NF-AT transcriptional activity.

Key Words: angiotensin II • calcineurin • gene regulation • hypertrophy • NF-AT • nuclear-localizing signals

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