Studies into novel therapies for the treatment of inflammatory artery disease

Abstract

The inflammatory artery diseases atherosclerosis and abdominal aortic aneurysm (AAA) are major causes of morbidity and mortality and there is significant attention towards identifying and targeting prominent inflammatory mediators underpinning these cardiovascular diseases. In the first chapter, the role of the pro-inflammatory and pro-oxidant enzyme myeloperoxidase (MPO) in inflammatory artery disease was studied. A clinical study showed that while circulating plasma MPO levels were not different in AAA patients versus healthy controls, immunohistochemistry showed that the MPO protein was prevalent in human AAA tissue. In the angiotensin II (AngII)-infusion model of AAA and atherosclerosis in apolipoprotein-E gene-deficient (ApoE–/–) mice, administration of 2-thioxanthines (2-TX), a clinically-trialled MPO inhibitor, significantly inhibited AAA but not atherosclerosis. Paradoxically, MPO gene-deficiency did not affect AngII-induced AAA but attenuated atherosclerosis. Notably, 2-TX significantly inhibited AAA in ApoE–/–MPO–/– mice, indicating 2-TX protects against aortic disease in the absence of MPO. The role of MPO in the diabetes-accelerated atherosclerosis in ApoE–/– mice was also examined. While MPO gene-deficiency did not impact on the degree of diabetes it significantly reduced diabetes-accelerated atherosclerosis at the brachiocephalic artery and aortic sinus, but not aortic arch, indicating that MPO exhibits site-specific effect on atherosclerosis. A second chapter focused on semicarbizide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a pro-inflammatory enzyme that facilitates the vascular recruitment of activated leukocytes. Treatment of AngII-infused ApoE–/– mice with a clinically-viable SSAO/VAP-1 inhibitor significantly protected against AAA and atherosclerosis, independent of alterations to plasma lipid levels. A third chapter tested the therapeutic efficacy of apolipoprotein A-I (ApoA-I), the major cardioprotective protein in high-density lipoproteins, and a class of immunomodulatory nanoparticles (INPs), which selectively target and disable a pro-inflammatory monocyte subset. Although ApoA-I treatment did not impact on the development of arterial disease in AngII-infused, aged ApoE–/– mice, INPs provided significant protection against AAA and atherosclerosis in these mice. This novel research provides new insights on the roles of MPO and SSAO in AAA and atherosclerosis and identified clinically-viable inhibitors of MPO and SSAO and a class of biodegradable immunomodulatory nanoparticles as potential new therapeutics for treating inflammatory artery disease.