Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases
Gabriel Choukroun, … , Anthony Rosenzweig, Thomas Force
Gabriel Choukroun, … , Anthony Rosenzweig, Thomas Force
Published August 15, 1999
Citation Information: J Clin Invest. 1999;104(4):391-398. https://doi.org/10.1172/JCI6350.
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Article

Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases

Abstract

Cardiac hypertrophy often presages the development of heart failure. Numerous cytosolic signaling pathways have been implicated in the hypertrophic response in cardiomyocytes in culture, but their roles in the hypertrophic response to physiologically relevant stimuli in vivo is unclear. We previously reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activated protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-1 in culture. We now report that gene transfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Furthermore, gene transfer of SEK-1(KR) inhibited pressure overload–induced cardiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV weight to body weight, cardiomyocyte diameter, and inhibition of atrial natriuretic factor expression. Our data suggest that the SAPKs are critical regulators of cardiac hypertrophy in vivo, and therefore may serve as novel drug targets in the treatment of hypertrophy and heart failure.

Authors

Gabriel Choukroun, Roger Hajjar, Stefanie Fry, Federica del Monte, Syed Haq, J. Luis Guerrero, Michael Picard, Anthony Rosenzweig, Thomas Force

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Inhibition of pressure overload–induced SAPK activation by gene transfer...
Inhibition of pressure overload–induced SAPK activation by gene transfer of SEK-1(KR). (a) Adenovirus-mediated gene transfer of SEK-1(KR) in the rat heart. Top: Three rats were transduced with AdLacZ and 3 with AdSEK-1(KR), as described in Methods and in ref. 20. After 72 hours, myocardial lysates were prepared and subjected to SDS-PAGE and immunoblotting with anti–SEK-1 antibody. Arrows identify endogenous SEK-1 and SEK-1(KR). Middle: The lysates from the rats injected with AdLacZ or AdSEK-1(KR) (above) were also blotted with anti-M2 mAb to confirm expression of M2–SEK-1(KR). Bottom: An additional 2 rats were sacrificed 24 hours after injection of AdLacZ or AdSEK-1(KR), and lysates were blotted with anti–SEK-1 antibody to confirm expression of the transgene at this earlier time point. (b) Inhibition of SAPK activation by SEK-1(KR). Animals were transduced with AdLacZ or AdSEK-1(KR), subjected to aortic banding, and sacrificed at 1, 3, or 7 days after banding. Immune-complex SAPK assays (left) or p38 assays (right) were performed. A representative experiment is shown below each graph. In the graph, kinase activity is expressed as fold increase in activity over that of control animals that were injected with vehicle and subjected to sham surgery. For each group, n = 4. Data are presented as mean ± SD. *P < 0.05 by Student’s t test for animals transduced with AdLacZ vs. sham control, and for AdLacZ vs. AdSEK-1(KR).