Inhibition of maladaptive cardiac hypertrophy by the Ras effector protein Rlf

Abstract

The monomeric G-protein Ras has been shown to have an obligatory role in the cardiac hypertrophic response by coordinating the activity of the mitogen activated protein kinases (MAPKs). Ras activation of ERK is associated with an adaptive hypertrophic response while JNK activation is associated with maladaptive hypertrophy. We identified the Ral guanine nucleotide dissociation stimulator like factor (Rlf) as a protein that binds to and interacts with Ras in cardiomyocytes. To understand the role of Rlf in regulating cardiomyocyte signaling, we assessed MAPK activation in neonatal rat ventricular myocytes (NRVMs) infected with adenoviruses encoding Rlf, or co-infected with constitutively active (V12-Ras) and Rlf. Rlf overexpression in NRVMs decreased agonist (endothelin-1 or phenylephrine) and V12-Ras mediated JNK activation without significantly altering ERK activation. To determine the effect of Rlf on cardiac hypertrophy in vivo, we generated transgenic mice with cardiac-specific overexpression of Rlf. Transgenic and nontransgenic male mice were treated with isoproteronol (ISO; 30 mg/kg/day) for 14 days. ISO treatment increased heart weight in transgenic and nontransgenic littermates to a similar extent. However, the hearts of Rlf transgenic mice treated with ISO displayed decreased fibrosis and myocardial cell loss compared to nontransgenic mice. Furthermore, Rlf transgenic mice were protected from ISO-mediated decreased SERCA2a expression. Overall, our results demonstrate that Rlf attenuates Ras-mediated activation of the JNK pathway and protects from maladaptive cardiac hypertrophy. (Supported by grants from the NIH and AHA)