Serine protease inhibitor A3 in atherosclerosis and aneurysm disease

Abstract

Abstract. Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe -/-mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl 2 -induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.

Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

“…Although CatG-mediated extracellular elastin degradation may contribute to atherogenesis, increased levels of the CatG inhibitor α1-anti-chymotrypsin in human and experimental atherosclerotic lesions [59] may limit secreted CatG’s contribution to elastin degradation in patients and animals with advanced atherosclerosis. In contrast, proteolysis of LDL by cell surface-associated CatG in various compartments protects the enzyme from α1-anti-chymotrypsin.…”

Serum Proteomic Analysis of Extracorporeal Shock Wave Therapy–Enhanced Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Model

“…Serine protease inhibitor A3 is an inhibitor of several proteases, such as elastase, cathepsin G, and chymase derived from mast cells and neutrophils. 38 Apolipoprotein A-IV is a component of lipoprotein particles similar to apolipoprotein E. 39 Concentrations of inflammatory protein have been shown to be associated with apolipoprotein A-IV, which suggests a link between inflammation and apolipoprotein A-IV synthesis or catabolism. 40,41 The downregulation of apolipoprotein A-IV precursor and serine protease inhibitor A3N found in serum of extracorporeal shock wavetreated rats should support the fact that they both are important factors in enhancing wound healing after extracorporeal shock wave therapy through suppression of the inflammatory response.…”

Elevation of Plasma High-Density Lipoproteins Inhibits Development of Experimental Abdominal Aortic Aneurysms

“…However, further investigation of the kinetics of expression, cell specificity, and functional activity of each of these genes in a variety of models is essential to fully understand their precise role in aneurysm pathobiology. For example, whereas SerpinA3n appears important in aneurysm formation, increasing circulating concentrations of Serpin A3n can inhibit early rupture of Ang II−induced aneurysms 57 but transgenic overexpression of 58 Interestingly, one of the latest new candidate genes, the angiopoietin-like protein 2, a member of the large family of secreted angiopoietins, shown to accelerate CaCl 2 -induced aneurysm formation 59 has also been shown to reduce plasma concentrations of HDLs through interaction with lipoprotein lipases. 60 These studies are proof of the concept that raising plasma concentration of HDLs has potential to reduce AAA.…”