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Clinical Investigation and Reports

Inhibitory Cardiac Transcription Factor, SRF-N, Is Generated by Caspase 3 Cleavage in Human Heart Failure and Attenuated by Ventricular Unloading

From the Departments of Molecular and Cellular Biology and Medicine, Division of Cardiovascular Sciences, Center for Cardiovascular Development, DeBakey Heart Center, Methodist Hospital, Baylor College of Medicine, Houston, Tex.

Correspondence to Dr Robert J. Schwartz, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail schwartz{at}bcm.tmc.edu

Received January 27, 2003; de novo received May 30, 2003; revision received June 12, 2003; accepted June 16, 2003.

Background— Knowledge about molecular mechanisms leading to heart failure is still limited, but reduced gene activities and modest activation of caspase 3 are hallmarks of end-stage heart failure. We postulated that serum response factor (SRF), a central cardiac transcription factor, might be a cleavage target for modest activated caspase 3, and this cleavage of SRF may play a dominant inhibitory role in propelling hearts toward failure.

Methods and Results— We examined SRF protein levels from cardiac samples taken at the time of transplantation in 13 patients with end-stage heart failure and 7 normal hearts. Full-length SRF was markedly reduced and processed into 55- and 32-kDa subfragments in all failing hearts. SRF was intact in normal samples. In contrast, the hearts of 10 patients with left ventricular assist devices showed minimal SRF fragmentation. Specific antibodies to N- and C-terminal SRF sequences and site-directed mutagenesis revealed 2 alternative caspase 3 cleavage sites, so that 2 fragments were detected of each containing either the N- or C-terminal SRF. Expression of SRF-N, the 32-kDa fragment, in myogenic cells inhibited the transcriptional activity of -actin gene promoters by 50% to 60%, which suggests that truncated SRF functioned as a dominant-negative transcription factor.

Conclusions— Caspase 3 activation in heart failure sequentially cleaved SRF and generated a dominant-negative transcription factor, which may explain the depression of cardiac-specific genes. Moreover, caspase 3 activation may be reversible in the failing heart with ventricular unloading.

Key Words: heart failure • serum response factor • apoptosis • heart-assist device

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