Nijholt, K.T. (Kirsten) (2018) A Kinase Interacting Protein 1 (AKIP1) regulates cardiomyocyte elongation and promotes physiological cardiac remodeling by activating the AKT/C-EBPβ/CITED4 pathway. thesis, Medicine.
Full text available on request.Abstract
Introduction: A Kinase Interacting Protein 1 (AKIP1) stimulates physiological cardiomyocyte hypertrophy in cultured cardiomyocytes but does not influence the cardiac response to pathological stress, suggesting that AKIP1 specifically regulates beneficial cardiac hypertrophy. Whether AKIP1 regulates the cardiac adaption to physiological stress in vivo is unknown. Purpose: To determine the effect of cardiomyocyte-specific overexpression of AKIP1 on the cardiac response to voluntary wheel running (VWR). Methods: Adult male mice with cardiomyocyte specific overexpression of AKIP1 (AKIP1-TG) or their wild type (WT) littermates were caged individually with or without the unlimited access to a running wheel (N=9-21/group). Exercise performance, heart weight/tibia length (HW/TL), cardiac MRI, cardiac histology, and left ventricular (LV) biochemistry were evaluated. Groups were compared by Two-way ANOVA. Results: Cardiac mass and function were comparable between sedentary WT and AKIP1-TG mice and the average running speed and distance were similar among genotypes. Cardiac hypertrophy induced by VWR was markedly augmented in AKIP1-TG vs WT mice as evidence by a 57 % greater increase in HW/TL and a 27 % greater increase in LV- mass on MRI. The estimated cardiomyocyte volume was also increased by 27% in AKIP1-TG vs WT mice, which was predominately determined by an increase in cardiomyocyte length (61.94 ± 5.35 μm vs 99.48 ± 2.18 μm; p<0.0001). The increase in cardiomyocyte elongation induced by VWR in AKIP1-TG mice was associated with a 6-fold increase in the phosphorylation of AKT, downregulation of C/EBPβ and the subsequent upregulation of mRNA and protein levels of CITED4. Conclusion: AKIP1 regulates cardiomyocyte elongation and physiological cardiac remodeling by activating the AKT/C-EBP/CITED4 pathway. These findings suggest that AKIP1 may serve as a nodal point for beneficial reprogramming of hypertrophic heart disease.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Faculty supervisor: and Westenbrink, Dr. B.D. and Second supervisor: and Sillje, dr. H.H.W. and Department of Experimental Cardiology and University Medical Center Groningen and University of Groningen |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:01 |
| Last Modified: | 25 Jun 2020 11:01 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2132 |
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