Local Signals and Macromolecular Architecture in Heart

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Heart Failure


T. B. Rogers
R. J. Bloch
W. J. Lederer

Molecular Genetics
Cell Biology 

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Project 2: Bloch

Stress-activated Protein Kinases
in the Regulation of Local Structure/Function
in the Cardiomyocyte

Approaches and Results

In order to study JNK signaling we have capitalized on state-of-the art genetic manipulations in the mouse. Using a JNK-activated transgenic mouse we have established the specific role of JNK activity in the regulation of the expression of a gap junction protein, connexin-43. In a collaborative immunohistochemistry study between Drs. Wang and Bloch, we demonstrated that JNK activation in myocardium led to specific loss of Cx43 protein at gap junctions without any significant effect on junctional proteins, such as N-caderin and ZO-. These results have suggested that down-regulation of Cx43 by JNK is a highly specific event.

This molecular pathology is being further explored in a new transgenic line with inducible JNK activation in adult myocardium. From this new animal model, we established the time frame for the progression of heart failure upon JNK activation in adult heart and observed interesting gender specific difference in life-span among the transgenic animals. In fact, males demonstrated more prevalent early death events than females using similar gene induction protocol. As shown in Figure 1, the progression of heart failure is associated with enlarged atria but limited changes in ventricular chamber size.

A study in collaboration with Dr. Lederer has determined the functional impact of JNK activation on cellular contraction, cellular fractional shortening, calcium transients and L-type calcium current in isolated myocytes using the conditional animal model to compare early versus late stages of JNK induction.



Click to view a larger image
Cardiomyopathy induced by JNK activation in vivo.
Development of cardiomyopathy upon JNK activation. (Wang).

Approaches and Results


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