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Title: The role of Extracellular-Regulated Protein Kinase 2 (ERK2) in cardiac hypertrophic remodelling
Author: Ulm, Susanne
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Cardiac hypertrophy is a response to increased mechanical demand on the heart. Initially hypertrophy is beneficial by reducing stress on the ventricular wall. However, sustained stress on the heart results in pathological hypertrophy which is characterised by re-induction of the fetal gene program, interstitial fibrosis, cardiomyocyte apoptosis, chamber dilation and eventually, heart failure. In contrast, exercise and pregnancy are considered to cause physiological hypertrophy with preservation of normal cardiac structure. The precise mechanism behind two different hypertrophy types remains unknown. In the heart mitogen-activated protein kinases (MAPKs) are involved in a complex signalling network. The extracellular-regulated protein kinase (ERK) 2 is one of classical MAPKs and shares with ERK1 an amino acid identity of 84%. Despite having many similarities, studies using total gene knockout mice clearly indicate that ERK1 and ERK2 have different roles and functions. ERK1 deficient knockout mice are fertile, viable and of normal size. Meanwhile, ERK2 knockout mice die during at embryonic day 6.5 to 11.5. Despite extensive studies the precise role of ERK1 and ERK2 (ERK1/2) in cardiac remodelling remains unclear. Since ERK2 contributes 70% to total ERK1/2 protein content, it is valuable to directly investigate the function of ERK2 in the heart. The use of cardiomyocyte-specific ERK2 deletion (ERK2cko) mice is one such approach compared to models inactivating or overexpressing ERK1/2 inhibitors and activators. The ERK2cko mice (generated in our lab) were fertile, viable and did not show any change in expression of other MAPKs in the heart or ERK2 in other tissues. To investigate the role of ERK2 in cardiac remodelling ERK2cko mice were exposed to different pathological and physiological hypertrophic stimuli. ERK2flox/flox (ERK2f/f) mice were used as a control group. β-adrenergic stimulation revealed a role of ERK2 in hypertrophy as ERK2cko mice showed less cardiomyocyte growth in comparison to ERK2f/f mice. However, no effect of ERK2 was observed on AngiotensinII-induced hypertrophy. After 1 week of pressure overload, the mutant mice showed less hypertrophic growth, less interstitial fibrosis and increased apoptosis compared to the controls. Long term pressure overload less increased hypertrophic growth and increased apoptosis in ERK2cko mice, which also showed early signs of heart failure. In concordance, neonatal rat cardiomyocytes infected with adenovirus expressing dominant negative ERK2 showed blunted hypertrophic growth and were more prone to apoptosis in vitro. In addition, ERK2 was not involved in physiological hypertrophy induced by 4 weeks swimming exercise. Taken together, ERK2 played an important role in cardiac hypertrophic remodelling induced by pressure overload and β-adrenergic stimulation where its absence led to blunted hypertrophic growth and sensitised cardiomyocytes to apoptosis. In contrast, ERK2 unlikely played a role in physiological hypertrophy induced by swimming exercise in our experimental setting.
Supervisor: Wang, Joy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available