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IQGAP1 regulates ERK1/2 and AKT signaling in the heart and sustains functional remodeling upon pressure overload

Mauro Sbroggiò, Daniela Carnevale, Alessandro Bertero, Giuseppe Cifelli, Emanuele De Blasio, Giada Mascio, Emilio Hirsch, Wadie F. Bahou, Emilia Turco, Lorenzo Silengo, Mara Brancaccio, Giuseppe Lembo, Guido Tarone
DOI: http://dx.doi.org/10.1093/cvr/cvr103 cvr103 First published online: 14 April 2011


Aims: The Raf-MEK1/2-ERK1/2 signaling cascade is crucial in triggering cardiac responses to different stress stimuli. Scaffold proteins are key elements in coordinating signaling molecules for their appropriate spatiotemporal activation. Here we investigated the role of IQGAP1, a scaffold for the ERK1/2 cascade, in heart function and remodeling in response to pressure overload.

Methods and Results: IQGAP1-null mice have unaltered basal heart function. When subjected to pressure overload, IQGAP1-null mice initially develop a compensatory hypertrophy indistinguishable from that of wild type mice. However, upon a prolonged stimulus, the hypertrophic response develops towards a thinning of left ventricular walls, chamber dilation, and a decrease in contractility, in an accelerated fashion compared to wild type mice. This unfavorable cardiac remodeling is characterized by blunted reactivation of the fetal gene program, impaired cardiomyocyte hypertrophy and increased cardiomyocyte apoptosis. Analysis of signaling pathways revealed two temporally distinct waves of both ERK1/2 and AKT phosphorylation peaking respectively at 10 minutes and 4 days after AB in wild type hearts. IQGAP1-null mice show strongly impaired phosphorylation of MEK1/2-ERK1/2 and AKT following 4 days of pressure overload, but normal activation these kinases after 10 min. Pull-down experiments indicated that IQGAP1 is able to bind the three components of the ERK cascade, namely c-Raf, MEK1/2 and ERK1/2, as well as AKT in the heart.

Conclusion: These data demonstrate, for the first time, a key role for the scaffold protein IQGAP1 in integrating hypertrophy and survival signals in the heart, and regulating long-term left ventricle remodeling upon pressure overload.