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Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload | Author(s) | John A. Muraski, Kimberlee M. Fischer, Weitao Wu, Christopher T. Cottage, Pearl Quijada, Matt Mason, Shabana Din, Natalie Gude, Roberto Alvarez, Jr., Marcello Rota, Jan Kajstura, Zeping Wang, Erik Schaefer, Xiongen Chen, Scott MacDonnel, Nancy Magnuson, Stephen R. Houser, Piero Anversa, Mark A. Sussman | | Journal | NAS, Sep 2008; 10.1073/pnas.0709135105. | Method Extract | | calcium contractility with a combined Ionoptix (fluorescence) and crescent (video edge detection) system | Abstract | | Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca2+ transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels. |
| Keywords | fluorescence, fluo-3 | Our Ref: 1698
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