Caspase-dependent Signaling as an Inductive Cue for Cardiac Hypertrophy

• Main Author: Putinski, Charis
• Other Authors: Megeney, Lynn
• Format: Others
• Language: en
• Published: Université d'Ottawa / University of Ottawa 2018
• Subjects: Cardiac Hypertrophy; Caspase
• Online Access: http://hdl.handle.net/10393/37728; http://dx.doi.org/10.20381/ruor-21992

The heart has the remarkable ability to adjust in response to varying stress stimuli and myocardium enlargement, referred to as cardiac hypertrophy, is a common form of stress adaptation. Divergent forms of hypertrophy can occur depending on the type and duration of the insult. The beneficial physiological form of hypertrophy is reversible and leads to improved cardiac function, while the pathological form is a maladaptive process that often transitions to heart failure. As a result of the prominence of cardiac disease, investigations into methods of reducing this detrimental form of cardiac remodeling are sought. Interestingly, pathological cardiac hypertrophy shares common features with the regulated form of cell death referred to as apoptosis. Here, we describe an essential role for apoptotic caspase-dependent signaling in the induction of pathological cardiac hypertrophy. Initially, we discovered that primary cardiomyocytes treated with hypertrophy agonists display transient activation of intrinsic-mediated apoptotic-signaling, including caspase 9 and caspase 3 activity. The necessity of functional caspase activation in hypertrophic signaling was shown by both in vitro and in vivo methods. We further investigated caspase cleavage targets histone deacetylase 3 (HDAC3) and gelsolin (GSN). HDAC3 cleavage was observed during early stages of hypertrophy and reduced in the presence of a caspase inhibitor. Caspase-mediated GSN cleavage occurred at latter stages, coincident with the cytoskeletal alterations that occur during this process. We demonstrated the requirement of GSN and its caspase-mediated processing by use of GSN expressing adenoviruses (AdVs). Use of a non-cleavable GSN-AdV provided evidence for not only the requirement of GSN in the hypertrophic response, but also for caspase mediated GSN cleavage. This body of work implicates caspase pathways and their targets as inductive signaling cues for pathological cardiac hypertrophy. These observations suggest that inhibitors that mute or suppress caspase activity and/or activity of its cognate substrates may offer novel therapeutic targets to limit the development of pathological hypertrophy.