Semicarbazide‐sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes‐like complications

Abstract

Semicarbazide-sensitive amine oxidases (SSAO) are copper-containing enzymes that oxidatively deaminate primary amines to produce hydrogen peroxide, ammonium, and specific aldehydes. Vascular adhesion protein-1 (VAP-1) is a cell surface and soluble molecule that possesses SSAO activity. VAP-1 protein, SSAO activity, and SSAO reaction products are elevated in the serum of patients with diabetes, congestive heart failure, and specific inflammatory liver diseases. By expressing human VAP-1/SSAO on mouse endothelial cells and subsequently in the serum, and by chronically treating the transgenic mice for 15 months with a high-fat diet and a physiological substrate for SSAO, methylamine, the in vivo roles of SSAO were assessed. The VAP-1 transgene increased the mouse body mass index and subcutaneous abdominal fat pad weights in a manner independent of food consumption. The transgene together with increased SSAO substrate availability enhanced glucose uptake in an SSAO-dependent manner. The increased SSAO activity also led to diabetes-like complications, including advanced glycation end product formation, elevated blood pressure, altered atherosclerosis progression, and nephropathy. These findings suggest that, although manipulation of VAP-1/SSAO has potential to serve as a therapeutic treatment in insulin-resistant conditions, care must be taken to fully understand its impact on obesity and vascular damage.

Soluble Vascular Adhesion Protein-1 Predicts Incident Major Adverse Cardiovascular Events and Improves Reclassification in a Finnish Prospective Cohort Study

“…The oxidase activity of VAP-1 induces the expression of other endothelial adhesion molecules (eg, P-selectin), 20 chemokines (eg, CXCL8), and transcription factors (eg, NF-kB). 21 The products of the catalytic reaction may also be involved in oxidation of lipids, in the production of reactive aldehydes 22 and advanced glycation end products, 23 and at high concentrations they can be directly cytotoxic. The structure of elastic fibers of tunica media is also regulated by VAP-1 in vivo.…”

Semicarbazide-sensitive amine oxidase and kidney disease

“…The VAP-1 molecule is a 170-to 180-kDa homodimeric glycoprotein that comprises two 90-kDa subunits held together by disulfide bonds. Experiments with transgenic and knockout mice have suggested that membrane-bound VAP-1 is the only source of plasma SSAO activity (90). Most serum SSAO activity disappears after the depletion of serum VAP-1 by anti-VAP-1 antibodies, further indicating that VAP-1 is the main source of circulating SSAO.…”

Function-blocking antibodies to human vascular adhesion protein-1: A potential anti-inflammatory therapy

“…To generate mTIEhVAP-1-transgenic/VAP-1-knockout (VAP KO+TG) mice, mTIEhVAP-1 line E35 mice expressing human VAP-1 on the vasculature [38] were crossed to VAP-1-knockout mice that were previously created by using conventional gene targeting techniques to replace the mouse VAP-1 gene with a nonfunctional mutant allele [11]. The mTIEhVAP-1-transgenic, mouse VAP-1 mutant allele and endogenous mouse VAP-1 allele were all identified by PCR screening of purified genomic DNA with specific primers and verified immunohistochemically with human and mouse VAP-1 antibodies [38].…”

“…The mTIEhVAP-1-transgenic, mouse VAP-1 mutant allele and endogenous mouse VAP-1 allele were all identified by PCR screening of purified genomic DNA with specific primers and verified immunohistochemically with human and mouse VAP-1 antibodies [38].…”