Abstract 16249: Acute Right Ventricular Pressure Overload Disrupts Organization of the Focal Adhesion Protein Talin
Right heart failure from acute right ventricular pressure overload (RVPO) is an important cause of morbidity and mortality, and currently has no specific therapy. We previously showed that RV dysfunction develops during brief RVPO in the absence of RV ischemia, persists after normal loading conditions are restored, and is attenuated by inhibition of the calcium activated protease calpain. Furthermore, RV dysfunction was strongly correlated with decreased abundance (by Western blotting) of the focal adhesion protein talin, a known target of calpain that links integrins to the cytoskeleton. We hypothesized that RVPO disrupts structure and organization of talin.
Methods: Anesthetized open chest pigs were subjected to 2 hrs acute RVPO (62±1 mmHg) without ischemia. High-speed drill biopsies of the RV free wall at baseline and after RVPO were cryosectioned transversely (10 μm), immunostained for talin, and optically sectioned (0.5 μm steps, 63x oil objective) with a digital deconvolution microscope.
Results: RVPO caused RV contractile dysfunction as previously reported. Deconvolved 2D optical sections (Fig 1) from 4 pigs at baseline (left) show that talin (red) exhibited a regular periodic structure localized to the myocyte surface; 3D reconstructions (Fig 2) showed talin organized in a longitudinal rib-like pattern. After RVPO (right), talin signal in 2D sections was irregular and fainter; in 3D reconstructions, talin ribs were blurred and disorganized.
Conclusions: RV pressure overload alters talin structure, probably through calpain activation. Calpain mediated talin disorganization may contribute to RV contractile dysfunction from acute RV pressure overload.
- © 2010 by American Heart Association, Inc.