Serpinc1/Antithrombin III Attenuates Salt-Induced Hypertension

Antithrombin III (ATIII), encoded by the gene Serpinc1 , is a serine protease inhibitor in the coagulation cascade and may inhibit inflammation and promote endothelial function. Serpinc1 is down-regulated in Dahl salt-sensitive (SS) rats compared to several rat strains with reduced blood pressure salt-sensitivity. The aim of this study was to investigate the role and the potential therapeutic effect of Serpinc1 /ATIII in salt-induced hypertension. ATIII activity was analyzed in patients with hypertension and the effect of Serpinc1 knockout or overexpression was examined in rat models. For mechanistic analysis, inflammation and endothelial function were examined. Lower ATIII activity is associated with higher blood pressure levels in hypertensive patients (n=90, P=0.015). Hypertension grades are also negatively correlated with ATIII activity (Spearman's coefficient r s =-0.2779, P=0.008). Heterozygous knockout of Serpinc1 in modestly salt-sensitive SS.13 BN26 rats exacerbated salt-induced hypertension (mean arterial pressure 141±5 mmHg in heterozygous knockout rats vs 128±2 mmHg in wild-type littermates after 14 days on a 4% NaCl diet, n=9 in heterozygous group and n= 10 in wild-type group, P<0.05). Serpinc1 overexpression in SS rats using adeno-associated virus (AAV) attenuated salt-induced hypertension (mean arterial pressure 142±7 mmHg in SS rats treated with AAV- Serpinc1 vs 189±13 mmHg in in SS rats treated with AAV-control after 14 days on a 4% NaCl diet, n=6 in AAV- Serpinc1 group and n= 5 in AAV-control group, P<0.05). Mechanistically, Serpinc1 insufficiency significantly increased renal outer medullary interleukin 6 mRNA and decreased endothelial nitric oxide synthase expression and endothelium-dependent vasodilation, while Serpinc1 overexpression had the opposite effect. Treatment of Serpinc1 heterozygous knockout rats with an interleukin 6 receptor antibody attenuated the exacerbation of salt-induced hypertension by Serpinc1 insufficiency. In conclusion, Serpinc1 /ATIII reduces inflammation, improves endothelial function, and attenuates salt-induced hypertension.