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Published on: February 13, 2019
Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction
Peter A Watson1, Nicholas Birdsey, Gordon S Huggins
1School of Medicine, Health Sciences Center, University of Colorado, Denver, Colorado 80045, USA. pete.watson@ucdenver.edu
Abstract:
Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415-2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-γ coactivator-1α and estrogen-related receptor-α content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and mortality. These results provide further support for the role of the CREB transcription factor in regulating mitochondrial integrity and identify a critical pathway that may contribute to sex differences in heart failure.
Insights
Female mice with dominant-negative CREB (dnCREB) show higher mortality and cardiac dysfunction due to mitochondrial issues. This highlights sex-based differences in heart failure progression and CREB
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Molecular Cardiology
Background:
- Cardiac failure is linked to reduced cyclic nucleotide regulatory element binding-protein (CREB) activity.
- Dominant-negative CREB (dnCREB) expression in the heart mimics cardiac failure phenotypes in mice.
Purpose of the Study:
- To investigate sex-specific effects of dnCREB expression on cardiac function and mitochondrial integrity.
- To elucidate the role of CREB in sex differences observed in heart failure.
Main Methods:
- Generation of heart-specific dnCREB transgenic mice.
- Assessment of survival rates, cardiac contractility, and mitochondrial function (respiratory capacity, density, structure).
- Measurement of reactive oxygen species (ROS) and antioxidant enzyme expression (MnSOD, glutathione peroxidase).
Main Results:
- Female dnCREB mice exhibited significantly higher mortality (17% vs. 67% in males) and contractile dysfunction.
- Mitochondrial respiratory capacity was diminished in both sexes by 4 weeks.
- Female dnCREB mice showed decreased mitochondrial density, structural deterioration, increased ROS, and reduced antioxidant expression by 12 weeks.
Conclusions:
- Heart-specific dnCREB expression causes mitochondrial respiratory dysfunction in both male and female mice.
- Female sex exacerbates mitochondrial oxidant burden, reduces antioxidant defenses, and disrupts mitochondrial structure, leading to greater cardiac morbidity and mortality.
- CREB plays a crucial role in maintaining mitochondrial integrity, and its dysregulation contributes to sex differences in heart failure.
