ENPP1 Q121 Variant, Increased Pulse Pressure and Reduced Insulin Signaling, and Nitric Oxide Synthase Activity in Endothelial Cells

• DOI: 10.1161/atvbaha.109.189191
• Publication Date: 2009-08-14T01:59:42Z
• Authors: Simonetta Bacci; Rosa Di Paola; Claudia Menzaghi; Patrizia Di Fulvio; Sara Di Silvestre; Fabio Pellegrini; Roberto Baratta; Antonella Marucci; Sandra Mastroianno; Grazia Fini; Gloria Formoso; Agostino Consoli; Francesco Perticone; Lucia Frittitta; Assunta Pandolfi; Vincenzo Trischitta
• Keywords: Adult; Male; Systole; Blood Pressure; 03 medical and health sciences; arterial stiffness; cardiovascular disease; endothelial dysfunction; enpp-1 gene; insulin resistance; 0302 clinical medicine; Humans; Insulin; Phosphorylation; Pyrophosphatases; Cells, Cultured; Polymorphism, Genetic; Phosphoric Diester Hydrolases; Endothelial Cells; Middle Aged; Receptor, Insulin; 3. Good health; Hypertension; Female; Insulin Resistance; Nitric Oxide Synthase; Proto-Oncogene Proteins c-akt; Signal Transduction

Objective—

Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk.

Methods and Results—

We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP ( P =8.0×10 −4 ). In the families, the Q121 variant accounted for 0.08 of PP heritability ( P =9.4×10 −4 ). This association was formally replicated in a second sample of 475 individuals ( P =2.6×10 −2 ) but not in 2 smaller samples of 289 and 236 individuals ( P =0.49 and 0.21, respectively). In the individual patients’ data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant ( P =1.2×10 −3 ). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation ( P =0.03), Ser 473 -Akt phosphorylation ( P =0.03), and NO synthase activity ( P =0.003).

Conclusions—

Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.