Using a gene-switch transgenic approach to dissect distinct roles of MAP kinases in heart failure.
We have demonstrated that Cre-loxP-mediated gene-switch transgenesis is an effective approach to achieve targeted and temporally regulated gene manipulation in the heart. Using this approach, we have established animal models with targeted activation of different MAPK pathways. From these animal models, we identified distinct features of cardiac pathology associated with individual MAPK branches (summarized in Fig. 8). Specifically, Ras activation appears to promote cardiac hypertrophy, whereas p38 and JNK activation does not. Whereas Ras activation leads to depressed diastolic function associated with suppressed calcium transients and SR calcium uptake, p38 activity seems to modulate cellular contractility without affecting intracellular calcium cycling. Although all three models displayed extensive remodeling in the myocardium, the extent and the composition of interstitial fibrosis are different among them, with Ras- and p38-activated hearts promoting collagen-based fibrosis, and JNK activation leading to induction in fibronectin-based reticular fiber. In addition, JNK activation leads to loss of Cx43 expression and abnormal cell-cell communication. Therefore, ERK, p38, and JNK are three distinct intracellular signaling pathways that contribute to different aspects of cardiac pathology during heart failure. Combining sophisticated genetic manipulation with comprehensive analysis at physiological, molecular, and genomic levels, the transgenic animals established in these studies should serve as valuable model systems to identify and dissect the underlying mechanisms for different aspects of cardiac pathology such as hypertrophy, contractile dysfunction, and abnormal cell-cell communication. The insights learned from these investigations may help to develop novel therapeutic approaches to confront this devastating disease.
Duke Scholars
Published In
DOI
ISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- ras Proteins
- Rats
- Myocytes, Cardiac
- Myocardial Contraction
- Mitogen-Activated Protein Kinases
- Mice, Transgenic
- Mice
- Humans
- Heart Failure
- Gene Expression Regulation, Enzymologic
Citation
Published In
DOI
ISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- ras Proteins
- Rats
- Myocytes, Cardiac
- Myocardial Contraction
- Mitogen-Activated Protein Kinases
- Mice, Transgenic
- Mice
- Humans
- Heart Failure
- Gene Expression Regulation, Enzymologic