Abstract 9: Apelin Protects Against Arterial Thrombosis in Mice with Diet-induced Obesity

Abstract

Background and Hypothesis The prevalence of obesity and related thrombotic diseases is increasing steadily, but the underlying mechanisms of thrombosis are not well elucidated. Apelin is a peptide adipokine that is upregulated in obesity and has protective effects on cardiovascular function. We tested the hypothesis that apelin protects from thrombosis in a mouse model of diet-induced obesity. Methods To induce obesity, male apelin null ( Apln -/y ) mice and wild-type (WT) littermates were fed a high fat (HF) diet with 60% of Kcal from fat (TD.06414) for 12 weeks. Susceptibility to thrombosis of the carotid artery was assessed using a photochemical injury (rose bengal) method. Expression of plasminogen activator inhibitor-1 (PAI-1) was measured by ELISA and real-time PCR. Results Body weight and fasting glucose were higher in mice fed the HF diet than in mice fed a control diet (P<0.05) but did not differ between Apln -/y and WT mice (P>0.05). The time to stable occlusion of the carotid artery was significantly accelerated in Apln -/y mice compared with WT mice (24.8±1.5 vs 43.9±6.8 min, P=0.04) fed the HF diet, but not a control diet. Because apelin is known to regulate the expression of the antifibrinolytic serpin PAI-1, we investigated the role of PAI-1 in the antithrombotic mechanism of apelin. Plasma levels of total PAI-1 were elevated 3-fold in WT mice fed the HF diet (P<0.05 vs. control diet). An even larger 5-fold elevation of plasma PAI-1 was seen in Apln -/y mice fed the HF diet (P<0.05). Levels of PAI-1 mRNA in lung also were significantly elevated in Apln -/y mice (P<0.01 vs. WT mice). To directly determine the role of PAI-1 in the prothrombotic phenotype of Apln -/y mice, a PAI-1-blocking antibody was administered prior to inducing thrombosis of the carotid artery. The PAI-1 antibody nearly completely reversed the shortened time to stable occlusion (P=0.03) in obese Apln -/y mice. Conclusions Endogenous apelin protects from arterial thrombosis in obesity, in part by dampening obesity-induced upregulation of PAI-1. These findings may have pharmacological implications for the prevention of thrombotic complications of obesity and metabolic syndrome.