Rationale: The pathogenesis and progression of pressure-overload heart failure (HF) encompasses aberrations in gene regulation, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. The trigger for maladaptation and HF is signaling through the G protein, Gq, and one downstream effector for this pathway is activation of non-canonical activity of G protein-coupled receptor kinase-5 (GRK5). This kinase, following hypertrophic stimuli, can translocate and accumulate in the nucleus of cardiomyocytes. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that can bind calmodulin (CaM), which is required before its nuclear translocation.
Objective: This study attempted to thwart GRK5-mediated pathology in pressure-overload maladaptation and HF by cardiomyocyte expression of a peptide encoding the NT of GRK5 (GRK5nt) that includes this CaM binding domain.
Methods and Results: In vitro studies in myocytes showed that Gq-coupled receptor mediated hypertrophy was abrogated with GRK5nt expression and this included attenuation of pathological gene expression and NFAT activity. We confirmed that the GRK5nt binds to Ca2+-CaM, prevents its association with endogenous GRK5, and prevents its nuclear translocation. We generated cardiac-specific GRK5nt transgenic mice and showed in vivo that expression of this peptide prevents hypertrophic nuclear translocation of GRK5 and these mice exhibit significantly less cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis following chronic transverse aortic constriction.
Conclusions: Together our data support a role for GRK5nt as an inhibitor of pathological nuclear GRK5 signaling for HF prevention. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/275 |
| Date | January 2020 |
| Creators | Coleman, Ryan |
| Contributors | Koch, Walter J, Tilley, Douglas G., Elrod, John W., Sabri, Abdelkarim, Schumacher-Bass, Sarah M. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 116 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/259, Theses and Dissertations |
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