Insulin-Regulated Increase of Soluble Vascular Adhesion Protein-1 in Diabetes

Abstract

Vascular adhesion protein-1 (VAP-1) is one of the molecules on the endothelial cell membrane, which may guide inflammatory cells into atherosclerotic lesions. This dual function molecule may also contribute to the pathogenesis of atherosclerosis and other vasculopathies via its enzymatic activity that oxidizes primary amines to produce their corresponding aldehydes, hydrogen peroxide, and ammonium. Because VAP-1 also exists in a soluble form, we analyzed its potential usefulness as a biomarker to monitor and predict the extent of ongoing atherosclerotic processes. Soluble VAP-1 (sVAP-1) levels were determined from the sera of 136 Finnish men with established coronary heart disease and in 275 controls using sandwich enzyme immunoassays and correlated to multiple risk factors for coronary events. Intriguingly, sVAP-1 showed a statistically significant correlation with diabetes in both cohorts. We then collected patients with type 1 diabetes and observed that sVAP-1 levels were highly elevated when the patients were metabolically compromised. On normalization of their blood glucose and ketone body levels by exogenous insulin, their sVAP-1 concentration rapidly decreased to control levels. Intravenous glucose tolerance and hyperinsulinemic clamp tests further showed that elevation of blood glucose per se did not increase sVAP-1 levels, but rather, sVAP-1 was inversely correlated with circulating insulin concentrations. In conclusion insulin appears to regulate shedding or clearance of VAP-1, and an increase in sVAP-1 because of absolute or relative insulin deficiency may be directly involved in the pathogenesis of diabetic angiopathy. (Am J Pathol 2002, 161:2255-2262)

Adipocytes release a soluble form of VAP-1/SSAO by a metalloprotease-dependent process and in a regulated manner

“…In keeping with these observations, we found that plasma SSAO activity was increased in Type 1 diabetic rats, as previously reported [12], but also in Type 1 diabetic mice and in Type 2 diabetic rats. The increments of SSAO activity associated with animal models of Type 1 and Type 2 diabetes are of a similar size to the increase of VAP-1 protein and SSAO activity previously reported in human diabetes [31,32,33]. If VAP-1/SSAO derives from adipose tissue, we can expect its plasma levels to increase in obesity or in insulin resistance.…”

“…Human, rat or murine plasma SSAO activity and VAP-1 concentrations are too low to directly detect the associated plasma protein by western blot. However, previous reports support the idea that soluble VAP-1 protein and soluble SSAO activity are identical, in as far as (i) the elimination of VAP-1 from human plasma by immunoaffinity is accompanied by a suppression of SSAO activity [34], and (ii) there is a correlation between the amount of VAP-1 protein determined by ELISA and the SSAO activity in serum from diabetic patients [32]. Taken together, our results from VAP-1 immunoprecipitation, the correlation found by us between VAP-1 protein and SSAO activity, and the above-mentioned, previously reported data strongly argue that (i) soluble VAP-1 protein and plasma SSAO activity are identical, and (ii) the presence of higher VAP-1 protein levels is associated with increased SSAO activity in diabetic rodents and humans.…”

“…We did not observe any direct influence of glucose itself or leptin on VAP-1/SSAO release. However, in this connection, it was recently reported that plasma glucose concentrations do not modulate plasmatic VAP-1/SSAO concentrations in humans [32]. Thus the increased serum VAP-1/SSAO in diabetes or obesity could, at least in part, be a consequence of insulin resistance promoted by TNF-α, whose action on the shedding of adipose tissue VAP-1/SSAO can be modulated by insulin.…”

“…VAP-1 is identical to semicarbazide-sensitive amine oxidase (SSAO) (EC 1.4.3.6) [23,24]. The soluble form of VAP-1/SSAO (sVAP-1/SSAO) is found in the serum of healthy adults in the range of 50 to 140 ng/ml and is increased in inflammatory liver diseases [4], cardiovascular pathologies [25], endstage renal disease [26], obesity [27,28], Type 1 diabetes [27,29,30,31,32] and Type 2 diabetes [27,31,33]. The membrane form of VAP-1/SSAO is highly expressed in endothelial cells, smooth muscle cells and adipose cells, which are strongly implicated in the pathology of atherosclerosis.…”

Crystallization of a truncated soluble human semicarbazide-sensitive amine oxidase

“…It has been suggested that some of the complications associated with diabetes, such as retinopathy, nephropathy, neuropathy, atherosclerosis and cardiovascular complications, may be caused by toxic products of SSAO-catalysed reactions (Ekblom, 1998;Kara  di et al, 2002;Salmi et al, 2002;Go È ktu È rk, Garpenstrand et al, 2003).…”