City Research Online

Abstract

Prolonged hypertension can cause hypertensive heart disease (HHD), characterised by cardiac hypertrophy and fibrosis, and is a major cause of heart failure (HF). Activation of CD47 by the matricellular protein, thrombospondin 1 (TSP1), can cause cellular stress by controlling NADPH oxidase 1 (NOX1) expression, which inhibits angiogenesis and promotes endothelial cell (EC) senescence; all mechanisms underpinning cardiac remodelling. One of the potential pathways linking CD47 to NOX1 are the mitogen-activated protein kinases (MAPKs), which include; p38-MAPK, JNK, and ERK1/2, each independently linked as effectors of stress processes. Furthermore, by negatively regulating MAPK signalling, dual specificity phosphatases (DUSPs) have recently been demonstrated to influence cardiac remodelling. However, whether the TSP1-CD47-NOX1 axis impairs cardiac endothelial function in HHD, and whether CD47 activation contributes to MAPK activation in the heart is entirely unknown. Moreover, it is not known whether DUSPs are dysregulated in HHD and can be influenced by CD47 signalling. Therefore, the aims of this project were to identify whether CD47 activation occurs in the hypertensive heart, to identify whether CD47 activation in the cardiac endothelium promotes stress signalling and can regulate DUSP expression.

This project identified that cardiac TSP1 expression was increased in patients with non-ischaemic HF and in mice with angiotensin II-induced hypertension. This project established that CD47 activation promoted NOX1 expression in cardiac ECs, which was found to be a novel instigator of impaired endothelial migration. Additionally, the results demonstrated that CD47 activation promoted MAPK activation in cardiac ECs and regulated the expression of DUSPs. Finally, the data indicated that the expression of cardiac DUSPs in non-ischaemic HF and in rodent models of hypertension was altered. From these results, it is proposed that blockade of CD47, inhibition of NOX1 or inhibition of DUSPs, may be novel strategies to ameliorate impaired cardiac endothelial function and thus cardiac remodelling in HHD.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > Q Science (General)
Departments:	School of Health & Medical Sciences > Cardiovascular and Genomics Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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