MAP3Ks in the heart: the role of cardiomyocyte BRAF in cardiac hypertrophy

Alharbi, H. O. (2023) MAP3Ks in the heart: the role of cardiomyocyte BRAF in cardiac hypertrophy. PhD thesis, University of Reading. doi: 10.48683/1926.00118756

Abstract/Summary

Intracellular mitogen-activated protein kinase (MAPK) signalling cascades play major roles in cardiac hypertrophy. RAF kinases are the mitogen-activated protein kinase kinase kinases (MAP3Ks) for the ERK1/2 pathway. RAF kinases are implicated in the regulation of ERK1/2 signalling in cardiomyocytes in response to hypertrophic stress and are associated with development of cardiac hypertrophy in vivo. However, the role of BRAF in cardiomyocyte hypertrophy is still to be established. To assess the mRNA and protein expression levels of MAP3Ks in hearts during postnatal development, hearts were harvested from Sprague-Dawley rats at 2, 7, 14 and 28 days of age and at 12 weeks. Data show that RAF kinases and the other MAP3K for the ERK1/2 pathway, Tpl2/Cot, are all expressed in the heart from postnatal development to adulthood. In addition, MAP3K family members, such as the MEKK, MLK and TAO families, ASK1/2 and TAK1 are all expressed in the heart during postnatal development. Furthermore, MAP3K2, MAP3K3, MAP3K13 and TAOK1 (of the MAP3Ks) were upregulated in heart samples from patients with heart failure compared with normal controls. To assess the role of cardiomyocyte BRAF in cardiomyocyte hypertrophy induced by the 1-adrenergic receptor agonist phenylephrine (PE), a mouse model with tamoxifen-inducible cardiomyocyte-specific BRAF deletion was used and the response determined in male and female mice. Heart function and dimensions were assessed by echocardiography and pathological changes assessed by histological staining of mouse heart sections. BRAF was not required for cardiomyocyte hypertrophy induced by PE over 7 d and there were no significant differences between the male and female response. However, loss of BRAF in cardiomyocytes increased the amount of fibrosis showing there was some abnormality. In conclusion, cardiomyocyte BRAF is playing an important role in heart development and adaptation of the heart to stress. However, in response to hypertrophy induced by PE, BRAF is not the main signalling pathway that drives cardiomyocyte hypertrophy.

Item Type	Thesis (PhD)
URI	https://reading-clone.eprints-hosting.org/id/eprint/118756
Identification Number/DOI	10.48683/1926.00118756
Divisions	Life Sciences > School of Biological Sciences
Download/View statistics	View download statistics for this item