Original sin: divine and symbolic violence in the turn to the Apostle Paul

When we take a step back from the imposing figure of physical violence, it becomes possible to examine other structurally violent forces that constantly shape our cultural and political landscapes. One of the driving interests in the “turn to Paul” in recent continental philosophy stems from wrestling with questions about the real nature of contemporary violence. Paul is positioned as a thinker whose messianic experience began to cut through the violent masquerade of the existing order. The crucifixion and resurrection of the Messiah (a slave and a God co-existing in one body) exposed the empty grounding upon which power resided. The Christ-event signifies a moment of violent interruption in the existing order which Paul enjoins the Gentiles to participate in through a dedication of love for the neighbour. This divine violence aims to reveal and subvert the “powers,” epitomised in the Roman Empire, in order to fulfil the labour of the Messianic now-time which had arrived. The impetus behind this research comes from a typically enigmatic and provocative section of text by the Slovene philosopher, cultural critic, and Christian atheist Slavoj Žižek. He claims that 'the notion of love should be given here all its Paulinian weight: the domain of pure violence… is the domain of love' (2008a, 173). In this move he links Paul’s idea of love to that of Walter Benjamin’s divine violence; the sublime and the cataclysmic come together in this seemingly perverse notion. At stake here is the way in which uncovering violent forces in the “zero-level” of our narrative worldviews aids the diagnosis of contemporary political and ethical issues. It is not enough to imagine Paul’s encounter with the Christ-event as non-violent. This Jewish apocalyptic movement was engaged in a violent struggle within an existing order that God’s wrath will soon dismantle. Paul’s weak violence, inspired by his fidelity to the Christ-event, places all responsibility over creation in the role of the individual within the collective body. The centre piece of this re-imagined construction of the Pauline narrative comes in Romans 13: the violent dedication to love understood in the radical nature of the now-time. 3 This research examines the role that narratives play in the creation and diagnosis of these violent forces. In order to construct a new genealogy of violence in Christianity it is crucial to understand the role of the slave of Christ (the revolutionary messianic subject). This turn in the Symbolic is examined through creating a literary structure in which we can approach a radical Nietzschean shift in Pauline thought. The claim here, a claim which is also central to Paul’s letters, is that when the symbolic violence which manipulates our worldviews is undone by a divine violence, if even for a moment, new possibilities are created in the opening for a transvaluation of values. Through this we uncover the nature of original sin: the consequences of the interconnected reality of our actions. The role of literature is vital in the construction of this narrative; starting with Cormac McCarthy’s No Country for Old Men, and continuing through works such as Melville’s Bartleby the Scrivener, this thesis draws upon the power of literature in the shaping of our narrative worlds. Typical of the continental philosophy at the heart of this work, a diverse range of illustrations and inspirations from fiction is pulled into its narrative to reflect the symbolic universe that this work was forged through. What this work attempts to do is give this theory a greater grounding in Paul’s letters by demonstrating this radical kenotic power at the heart of the Christ-event. Romans 13 reveals, in a way that has not yet been picked up by Critchley, Žižek, and others, that Paul opposed the biopolitical power of the Roman Empire through the weak violence of love that is the labour of the slaves of Christ on the “now-time” that had arrived.

Investigating Angiotensin II in cardiac remodelling and the counter-regulatory actions of Angiotensin-(1-9)

Cardiovascular diseases (CVDs) including, hypertension, coronary heart disease and heart failure are the leading cause of death worldwide. Hypertension, a chronic increase in blood pressure above 140/90 mmHg, is the single main contributor to deaths due to heart disease and stroke. In the heart, hypertension results in adaptive cardiac remodelling, including LV hypertrophy to normalize wall stress and maintain cardiac contractile function. However, chronic increases in BP results in the development of hypertensive heart disease (HHD). HHD describes the maladaptive changes during cardiac remodelling which result in reduced systolic and diastolic function and eventually heart failure. This includes ventricular dilation due to eccentric hypertrophy, cardiac fibrosis which stiffens the ventricular wall and microvascular rarefaction resulting in a decrease in coronary blood flow albeit an increase in energy demand. Chronic activation of the renin-angiotensin-system (RAS) with its effector peptide angiotensin (Ang)II plays a key role in the development of hypertension and the maladaptive changes in HHD. Ang II acts via the angiotensin type 1 receptor (AT1R) to mediate most of its pathological actions during HHD, including stimulation of cardiomyocyte hypertrophy, activation of cardiac fibroblasts and increased collagen deposition. The counter-regulatory axis of the RAS which is centred on the ACE2/Ang-(1-7)/Mas axis has been demonstrated to counteract the pathological actions of Ang II in the heart and vasculature. Ang-(1-7) via the Mas receptor prevents Ang II-induced cardiac hypertrophy and fibrosis and improves cardiac contractile function in animal models of HHD. In contrast, less is known about Ang-(1-9) although evidence has demonstrated that Ang-(1-9) also antagonises Ang II and is anti-hypertrophic and anti-fibrotic in animal models of acute cardiac remodelling. However, so far it is not well documented whether Ang-(1-9) can reverse established cardiac dysfunction and remodelling and whether it is beneficial when administered chronically. Therefore, the main aim of this thesis was to assess the effects of chronic Ang-(1-9) administration on cardiac structure and function in a model of Ang II-induced cardiac remodelling. Furthermore, this thesis aimed to investigate novel pathways contributing to the pathological remodelling in response to Ang II. First, a mouse model of chronic Ang II infusion was established and characterised by comparing the structural and functional effects of the infusion of a low and high dose of Ang II after 6 weeks. Echocardiographic measurements demonstrated that low dose Ang II infusion resulted in a gradual decline in cardiac function while a high dose of Ang II induced acute cardiac contractile dysfunction. Both doses equally induced the development of cardiac hypertrophy and cardiac fibrosis characterised by an increase in the deposition of collagen I and collagen III. Moreover, increases in gene expression of fibrotic and hypertrophic markers could be detected following high dose Ang II infusion over 6 weeks. Following this characterisation, the high dose infusion model was used to assess the effects of Ang-(1-9) on cardiac structural and functional remodelling in established disease. Initially, it was evaluated whether Ang-(1-9) can reverse Ang II-induced cardiac disease by administering Ang-(1-9) for 2-4 weeks following an initial 2 week infusion of a high dose of Ang II to induce cardiac contractile dysfunction. The infusion of Ang-(1-9) for 2 weeks was associated with a significant improvement of LV fractional shortening compared to Ang II infusion. However, after 4 weeks fractional shortening declined to Ang II levels. Despite the transient improvement in cardiac contractile function, Ang-(1-9) did not modulate blood pressure, LV hypertrophy or cardiac fibrosis. To further investigate the direct cardiac effects of Ang-(1-9), cardiac contractile performance in response to Ang-(1-9) was evaluated in the isolated Langendorff-perfused rat heart. Perfusion of Ang-(1-9) in the paced and spontaneously beating rat heart mediated a positive inotropic effect characterised by an increase in LV developed pressure, cardiac contractility and relaxation. This was in contrast to Ang II and Ang-(1-7). Furthermore, the positive inotropic effect to Ang-(1-9) was blocked by the AT1R antagonist losartan and the protein kinase A inhibitor H89. Next, endothelial-to-mesenchymal transition (EndMT) as a novel pathway that may contribute to Ang II-induced cardiac remodelling was assessed in Ang II-infused mice in vivo and in human coronary artery endothelial cells (HCAEC) in vitro. Infusion of Ang II to mice for 2-6 weeks resulted in a significant decrease in myocardial capillary density and this was associated with the occurrence of dual labelling of endothelial cells for endothelial and mesenchymal markers. In vitro stimulation of HCAEC with TGFβ and Ang II revealed that Ang II exacerbated TGF-induced gene expression of mesenchymal markers. This was not correlated with any changes in SMAD2 or ERK1/2 phosphorylation with co-stimulation of TGFβ and Ang II. However, superoxide production was significantly increased in HCAEC stimulated with Ang II but not TGFβ. Finally, the role of Ang II in microvesicle (MV)-mediated cardiomyocyte hypertrophy was investigated. MVs purified from neonatal rat cardiac fibroblasts were found to contain detectable Ang II and this was increased by stimulation of fibroblasts with Ang II. Treatment of cardiomyocytes with MVs derived from Ang II-stimulated fibroblasts induced cardiomyocyte hypertrophy which could be blocked by the AT1R antagonist losartan and an inhibitor of MV synthesis and release brefeldin A. Furthermore, Ang II was found to be present in MVs isolated from serum and plasma of Ang II-infused mice and SHRSP and WKY rats. Overall, the findings of this thesis demonstrate for the first time that the actions of Ang-(1-9) in cardiac pathology are dependent on its time of administration and that Ang-(1-9) can reverse Ang II-induced cardiac contractile dysfunction by acting as a positive inotrope. Furthermore, this thesis demonstrates evidence for an involvement of EndMT and MV signalling as novel pathways contributing to Ang II-induced cardiac fibrosis and hypertrophy, respectively. These findings provide incentive to further investigate the therapeutic potential of Ang-(1-9) in the treatment of cardiac contractile dysfunction in heart disease, establish the importance of novel pathways in Ang II-mediated cardiac remodelling and evaluate the significance of the presence of Ang II in plasma-derived MVs.