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Caspase-3 Activity in the Rat Amygdala Measured by Spectrofluorometry After Myocardial Infarction
08:41

Caspase-3 Activity in the Rat Amygdala Measured by Spectrofluorometry After Myocardial Infarction

Published on: January 12, 2016

Inhibitory cardiac transcription factor, SRF-N, is generated by caspase 3 cleavage in human heart failure and

Jiang Chang1, Lei Wei, Takayuki Otani

  • 1Department of Molecular and Cellular Biology, Center for Cardiovascular Development, Methodist Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, Tex 77030, USA.

Circulation
|July 23, 2003
PubMed

Insights

In heart failure, caspase 3 cleaves serum response factor (SRF), creating a dominant-negative factor that suppresses cardiac genes. This SRF cleavage may be reversible with ventricular unloading.

Area of Science:

  • Molecular biology
  • Cardiovascular research
  • Biochemistry

Background:

  • Heart failure is characterized by reduced gene activity and modest caspase 3 activation.
  • The role of the cardiac transcription factor serum response factor (SRF) in heart failure is not fully understood.
  • We hypothesized that caspase 3 cleaves SRF, inhibiting its function and contributing to heart failure.

Purpose of the Study:

  • To investigate whether serum response factor (SRF) is a cleavage target of caspase 3 in end-stage heart failure.
  • To determine the functional consequences of SRF cleavage in the failing heart.

Main Methods:

  • Analysis of SRF protein levels and fragmentation in human cardiac samples from heart failure patients and normal controls.
  • Investigation of SRF fragmentation in patients with left ventricular assist devices.
  • Identification of caspase 3 cleavage sites on SRF using antibodies and site-directed mutagenesis.
  • Assessment of the transcriptional activity of SRF fragments in myogenic cells.

Main Results:

  • Full-length SRF was significantly reduced and fragmented in failing hearts but intact in normal hearts.
  • Minimal SRF fragmentation was observed in hearts with left ventricular assist devices.
  • Two alternative caspase 3 cleavage sites were identified, generating N-terminal and C-terminal SRF fragments.
  • Expression of the 32-kDa N-terminal SRF fragment (SRF-N) inhibited alpha-actin gene promoter activity by 50-60%.

Conclusions:

  • Caspase 3 activation in heart failure sequentially cleaves SRF, producing a dominant-negative transcription factor.
  • This process may explain the downregulation of cardiac-specific genes in heart failure.
  • Caspase 3 activation and subsequent SRF cleavage might be reversible upon ventricular unloading.
Abstract

Keywords:
Non-programmatic

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