Abstract 268: Adiponectin Antagonizes the Stimulatory Effect of TNF3 on Vascular Smooth Muscle Cell Calcification
Vascular calcification presents important clinical implications in cardiovascular disease. Recently, we have reported that growth arrest-specific gene 6 (Gas6) and its receptor, Axl mediated-survival pathway plays a pivotal role in inorganic phosphate (Pi)-induced vascular smooth muscle cell (VSMC) calcification. In the present study, we investigated the effect of anti-atherogenic adipokine, adiponectin, and atherogenic adipokine, TNFα, on VSMC calcification.
<Methods and Results> In human VSMC, TNFα augmented Pi-induced apoptosis measured by DNA fragmentation and calcification measured by calcium deposit in a concentration (0.5–50 ng/ml)-dependent manner, whereas adiponectin significantly suppressed Pi-induced apoptosis and calcification in a concentration (3–300 ng/ml)-dependent manner. More interestingly, adiponectin abolished the stimulatory effect of TNFα on apoptosis and calcification in a concentration-dependent manner. Adiponectin restored the expression of Gas6 downregulated by TNFα, but did not affect the expression of Axl reduced by TNFα. Reporter assay using the -1.9 kb Gas6-luciferase DNA construct revealed that adiponectin rescued the decrease in Gas6 promoter activity by TNFα. Inhibition of AMP-activated protein kinase using chemical inhibitor, compound C, abrogated the effect of adiponectin on Gas6 expression, apoptosis and calcification. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFα on VSMC calcification by activating Gas6 transcription.